CET - Center for Environmental Therapeutics

THE RESEARCH AGENDA

Research Initiatives Supported by the U.S. National Institutes of Health

The Center for Environmental Therapeutics — with its interest areas in nonpharmacologic treatment of depression, sleep disorders and daytime fatigue — has identified a wide range of relevant research projects currently supported by the National Institutes of Health. Below we list a selection of 22 investigations cited in NIH's CRISP database: for a full listing, you can access CRISP by logging onto http://crisp.cit.nih.gov/and searching by key words such as light therapy, depression, sleep disorders, circadian rhythms, and melatonin. Although our selection is restricted to studies of human subjects, CRISP also includes a host of relevant basic research studies using animal subjects and biological materials.

Investigator's Name: CAMPBELL, SCOTT S.

Project Title: BRIGHT LIGHT TREATMENT OF SLEEP DISTURBANCE IN ELDERLY

Abstract: It is widely recognized that changes in the sleep/wake system accompany the aging process. As a consequence, a large proportion of older people complain of significant sleep disturbance-Age-related sleep changes are commonly expressed as shallow and fragmented sleep, and multiple, often prolonged awakenings, particularly in the second half of the night. Few older subjects report difficulties getting to sleep. Therefore, sleep disturbance in people over 65 is generally considered to be a disorder of maintaining, rather than initiating, sleep. Recent evidence indicates that timed exposure to bright light can be effective in managing these age-related sleep changes by acting directly on the circadian timing system. Yet, effectiveness, of light treatment may be compromised by compliance problems associated with the time required for, and the constraints involved in, the treatment regimen. Response to treatment is likely to be affected also by one's recent history of light exposure. Until issues of compliance are fully understood and effectively dealt with, light treatment for age-related sleep disturbance cannot be employed to its full potential. This COMPETING CONTINUATION will examine three important issues related to compliance: First, it is proposed to quantify the effects of prior light history on the phase-shifting capacity of bright light. Second, a novel procedure for light delivery will be tested, the development of which may hold promise for significantly enhancing user compliance. Finally, an in-home treatment will be implemented which administers light in a manner that may be more acceptable to patients. In the lab-based studies, circadian variables of young (<30 yrs) and older subjects (>65 yrs) will be monitored at baseline, and throughout an interval during which subjects' prior light history is controlled, immediately preceding exposure to 1) a conventionally-administered bright light phase-shifting stimulus, or 2) a bright light phase-shifting stimulus administered using a non-ocular site for phototransduction. In the treatment study, two groups of healthy, older subjects (>65 yrs) who complain of sleep maintenance insomnia, and whose complaints are verified polygraphically, will undergo either 1) a one-month regimen of timed room-light exposure combined with timed light avoidance, or 2) a well-validated control condition, while living at home and continuing normal daily activities. All three studies address issues crucial to the successful development and implementation of bright light treatment.

Institution: WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY, NEW YORK, NY 10021, Department: PSYCHIATRY
Funding Agency: NATIONAL INSTITUTE OF MENTAL HEALTH
Investigator's Name: CZEISLER, CHARLES A.

Project Title: BRIGHT LIGHT TREATMENT OF SHIFT ROTATION INSOMNIA

Abstract: More than one-third of working men and one-quarter of working women in the U. S. report being exposed to a variable schedule that includes both day and night work. Of these, approximately 7.3 million must regularly work overnight, either on permanent night shifts or rotations between day, evening, and night shifts, requiring them to forego nocturnal sleep and attempt to sleep during the day. Despite this nocturnal deprivation of sleep, these workers typically experience daytime insomnia, leading to diminished alertness and cognitive performance and increased sleep tendency during waking hours at night. In fact, 55 percent of night shift workers report nodding off or falling asleep at work at least once per week, with more than 30 percent reporting that such incidents occur more than three times per week. Recent research has demonstrated that properly timed exposure to bright light and darkness can rapidly reset the human circadian pacemaker that-controls the timing of the sleep-wake cycle, enabling the circadian pacemakers of individuals working at night to fully adapt to their desired schedules within 2-3 days. On the basis of these results, four testable hypotheses are proposed: (l) that bright light can rapidly shift the endogenous circadian rhythms of plasma melatonin secretion of individuals working at night, such that their circadian timing system remains adapted to their inverted sleep-wake schedule; (2) that bright light can increase sleep efficiency, and reduce the number and duration of awakenings during the daytime sleep of individuals working at night; (3) that bright light can reduce the frequency of involuntary microsleep episodes and decrease sleep propensity during scheduled wakefulness at night; and (4) that bright light can improve the alertness and cognitive performance of individuals working at night. An experiment is proposed to evaluate the impact of bright light treatment on the daytime sleep and nocturnal cognitive performance of individuals during a combined laboratory- and field-based simulation of a complete, 3- month shift rotation. Subjects exposed to an appropriate schedule of bright light while working in the laboratory will be compared to a control group of subjects without bright light exposure. Sleep, activity, and light exposure will be monitored with ambulatory recording devices, circadian phase will be assessed from serum melatonin levels, and cognitive performance will be evaluated with a computer-administered battery of tests. This work has significant implications for shiftworker health and population safety. Shiftwork is associated with cardiovascular disease, depression, increased drug use, and digestive disorders. Many catastrophic accidents (e.g., Exxon Valdez, Bhopal, Three-Mile Island, Chernobyl) have occurred during the night shift with fatigue identified as a contributor. An effective countermeasure to the personal and societal risks of shiftwork could substantially improve public health and safety.

Institution: BRIGHAM AND WOMEN'S HOSPITAL, 75 FRANCIS ST, BOSTON, MA 02115
Funding Agency: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Investigator's Name: CZEISLER, CHARLES A.

Project Title: CIRCADIAN ADAPTATION TO NIGHT WORK IN OLDER PEOPLE

Abstract: Night and rotating shift work schedules induce misalignment between the phase of the circadian pacemaker and the work/sleep schedule, leading to excessive fatigue at work and disrupted daytime sleep in night workers. Also, night work often begins after more extended wakefulness than daytime work. This combination leads to sleepiness, errors, and injuries on the night shift, as well as health problems. These effects are worse for older workers. While we have shown that treating young subjects with bright light and a fixed morning sleep schedule results in rapid circadian adaptation to night work, preliminary studies indicate that this strategy will be ineffective for older people, whose sleep is more sensitive to incomplete circadian adaptation to delayed sleep schedules. Given the increasing median age of the workforce, it is critical to develop shift work effective countermeasures for the older worker. We hypothesize that phase advancing the sleep episode and circadian rhythm will be a more effective strategy in older workers. We propose three testable hypotheses: that 1) older subjects who work 3 successive night shifts and sleep ad lib will suffer from misalignment between their work/sleep schedule and their circadian phase, disrupted daytime sleep, and degraded night shift performance relative to the day shift; 2) in older subjects who are scheduled to sleep in the morning after their night shifts, working 3 successive nights in bright light during the beginning of the night shift will improve alignment between the work/sleep cycle and the circadian melatonin rhythm compared to working 3 successive night shifts in standard room light, without the corresponding improvement in sleep and night shift performance that has been observed in young subjects; and, 3) in older subjects who are scheduled to sleep in the evening before their night shifts, working 3 successive nights in bright light during the late hours of the night shift will improve alignment between the work/sleep cycle and the circadian melatonin rhythm compared to working 3 successive night shifts in standard room light, with a corresponding improvement in sleep and night shift performance. We propose an experiment to evaluate the effects of two regimens combining bright light treatment and scheduled sleep on circadian melatonin rhythms, sleep, performance in older individuals in a laboratory simulation of night work. We propose to measure activity and light exposure with ambulatory devices, circadian phase using salivary melatonin levels, sleep via polysomnography, and performance by computerized tests. This work has major implications for the health and safety of older shift workers.

Institution: BRIGHAM AND WOMEN'S HOSPITAL, 75 FRANCIS ST, BOSTON, MA 02115
Funding Agency: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Investigator's Name: ROSENTHAL, N E.

Project Title: CLINICAL ASPECTS OF WINTER SEASONAL AFFECTIVE DISORDER

Abstract: The clinical profile of seasonal affective disorder (SAD), a recurring condition of winter depressions and summer remissions which we first described over a decade ago, has been widely corroborated. Likewise, light therapy, which we first found be an effective treatment for SAD, has become a mainstream psychiatric treatment. We continue to study novel aspects of the clinical profile of SAD patients and effectiveness of light therapy. Publications of relevance to these topics during the past year include findings that: (1) light therapy, combined with dawn simulation, is superior to a control condition in reversing depressive symptoms in children and adolescents with SAD and (2) in a small number of subjects, a head-mounted light visor was as effective as light box at maintaining the antidepressant effects of light therapy for at least one week.

Institution: National Institute of Mental Health, Bethesda, MD
Funding Agency: NATIONAL INSTITUTE OF MENTAL HEALTH
Investigator's Name: KRIPKE, DANIEL F.

Project Title: PHASE RESPONSE CURVES FOR EXERCISE AND BRIGHT LIGHT

Abstract: The investigator's laboratory has discovered an appalling prevalence of malsynchronization of circadian rhythms among volunteers averaging 70 years of age. Aging people may be abnormally resistant to the circadian synchronizing effects of bright light. If so, we may need to develop alternative methods by which older Americans can synchronize their circadian rhythms to the environment. Recent studies indicate that exercise may shift circadian rhythms in young adults, but nothing is known about the value of exercise for regulating circadian rhythms in the aging population. It seems crucial to extend our understanding of exercise effects on the circadian system and, specifically, to compare the potential values of exercise and bright light for correcting the circadian malsynchronization of older Americans. The project will establish circadian phase response curves both for exercise and for bright light in 96 volunteers, ages 18-30 plus 128 older volunteers ages 60-75 years. Volunteers will be recorded for 4.8 to 4.6 days while following an ultra-short sleep-wake cycle, consisting of 30 minutes for sleeping, followed by 60 minutes for waking. Baseline circadian phases of urinary 6-sulphatoxymelatonin, urinary free cortisol, temperature and sleep propensity will be assessed every 90 min. Oral temperature will be sampled every 30 min. Volunteers will be given experimental phase-shifting treatments (exercise or bright light) for 3 days. Resultant circadian phases will then be determined to compute the phase response curves, in order to examine interactions of stimulus (exercise vs. light), age, and gender on circadian responsiveness.

Institution: UNIVERSITY OF CALIFORNIA SAN DIEGO, GILMAN & LA JOLLA VILLAGE DR, SAN DIEGO, CA 92093
Funding Agency: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Investigator's Name: WEHR, THOMAS A.

Project Title: INVESTIGATION OF MELATONIN AS A CHEMICAL TRIGGER OF WINTER DEPRESSION

Abstract: Melatonin is secreted exclusively at night, and the duration of its secretion is proportional to the duration of night--longer in winter and shorter in summer. Animals use these seasonal changes in the duration of nocturnal melatonin secretion as a chemical signal to regulate the timing of seasonal changes in their behavior. Long nightly periods of secretion trigger winter-type behaviors, while short nightly periods of secretion trigger summer-type behaviors. In this project, we are testing the hypothesis that the seasonal melatonin signal (i.e., change in duration of its nightly secretion) is part of the mechanism that triggers winter depression in individuals who suffer from seasonal affective disorder (SAD). In animals, the melatonin response to seasonal change in nightlength has been shown to be mediated by a clearly defined neural circuit that originates in the retina and terminates in the pineal gland. The initial transduction of the photic signal appears to be mediated by novel opsins in the retina. The timing of melatonin secretion is programmed by circadian pacemaker cells in the suprachiasmatic nucleus (SCN) of the hypothalamus, which receives retinal input and acts on the pineal via a multi-synaptic pathway. The SCN pacemaker appears to contain two components, one (E) that is synchronized with dusk and controls the evening onset of melatonin secretion and another (M) that is synchronized with dawn and controls the morning offset of melatonin secretion. Downstream responses to changes in duration of nocturnal melatonin secretion are mediated by G-protein-coupled melatonin-receptors in the pars tuberalis and elsewhere. To test the melatonin hypothesis of the pathogenesis of recurrent winter depression, we are carrying out a series of related studies. In the current project, 24-hour profiles of melatonin secretion are assessed twice, once in winter and once in summer, in patients with recurrent winter depression and in healthy controls matched for age, sex and menstrual status. For each melatonin assessment, individuals are admitted to a research unit and remain in a dark room for 24 hours while blood samples are obtained through an indwelling venous catheter. Plasma samples are subsequently be assayed for levels of melatonin. Our previous research has shown that the human retinohypothalamic-pineal axis has conserved a capacity to detect seasonal changes in the length of the night and to use this information to make proportional adjustments in the intrinsic duration of nocturnal melatonin secretion (the duration in constant dim light). The purpose of the present project is to determine whether and to what extent healthy volunteers and patients with SAD respond in this way to seasonal changes in the natural scotoperiod when they live in a modern urban environment in which they are exposed to ambient artificial light after dark. A failure of patients with SAD to exhibit seasonal changes in the duration of nocturnal melatonin secretion would indicate that the SCN is not registering seasonal changes in duration of the natural photoperiod and would falsify the classical melatonin hypothesis of pathogenesis of the disorder. One hundred and nineteen individuals have been studied. So far, results support the melatonin hypothesis of the pathogenesis of recurrent winter depression in men with seasonal affective disorder but not in women. In men with SAD, in contrast to healthy men, the intrinsic duration of nocturnal melatonin secretion is longer in winter than in summer, and this difference is highly statistically significant. This gender difference in our findings may be consistent with several other kinds of evidence indicating that mechanisms responsible for the pathogenesis of SAD may differ in men and women. A second, and unexpected finding was that most of the variance between winter and summer duration of nocturnal melatonin secretion can be attributed to winter-summer changes in the timing of morning offset of secretion, and not timing of onset of secretion. This finding may help to explain the now well-established clinical finding that morning light is more effective than evening light in the treatment of winter depression. It is also consistent with a recent finding that changes in the duration of the photoperiod to which rodents have been exposed selectively modifies electrical activity recorded in the SCN in vitro in the morning.

Institution: National Institute of Mental Health, Bethesda, MD
Funding Agency: NATIONAL INSTITUTE OF MENTAL HEALTH
Investigator's Name: ROSENTHAL, N E.

Project Title: CLINICAL ASPECTS OF WINTER SEASONAL AFFECTIVE DISORDER

Abstract: The clinical profile of seasonal affective disorder (SAD), a recurring condition of winter depressions and summer remissions which we first described over a decade ago, has been widely corroborated. Likewise, light therapy, which we first found be an effective treatment for SAD, has become a mainstream psychiatric treatment. We continue to study novel aspects of the clinical profile of SAD patients and effectiveness of light therapy. Publications of relevance to these topics during the past year include findings that: (1) light therapy, combined with dawn simulation, is superior to a control condition in reversing depressive symptoms in children and adolescents with SAD and (2) in a small number of subjects, a head-mounted light visor was as effective as light box at maintaining the antidepressant effects of light therapy for at least one week.

Institution: National Institute of Mental Health, Bethesda, MD
Funding Agency: NATIONAL INSTITUTE OF MENTAL HEALTH
Investigator's Name: TERMAN, MICHAEL

Project Title: LIGHT/ION THERAPY FOR SEASONAL AFFECTIVE DISORDER

Abstract: Two new environmental treatments for the winter depression of seasonal affective disorder (SAD) -- naturalistic dawn simulation and negative air ionization -- will receive clinical trials including placebo controls and a comparison with bright light therapy (an established treatment for SAD). Dawn simulation is a gradually-increasing dim light signal with an accelerating rate of change during the final hours of sleep. Artificially produced high-density negative air ions permeate the ambient circulation but are not directly detectable by sensation. Both treatments contrast withpost-awakening bright light therapy, and offer potential advantages in scheduling and minimization of side effects. Placebo response rates often have been substantial in bright light studies. The present proposal introduces two new controls, non-incremental light pulses with photon emission equated with that of the dawn, and low-density negative ions. With subjects randomized into 5 parallel treatment groups (3 active, 2 placebo), the placebos will serve as controls for clinical response on both dimensions (light, ions). Based on our preliminary positive results using the investigational treatments, redesigned apparatus will standardize doses: the dawn signal will be diffused from an overhead fixture that evenly fills the sleeping area with light, and closed-loop dosimetry will provide precise control of ion flow rate to the subject. Treatment scheduling will be based on an estimate of circadian phase while subjects are depressed, using sleep log data correlated with the nocturnal melatonin secretion marker. The magnitude of pre- to post treatment phase shifts will be compared with the degree of clinical improvement as assessed by depression rating scales. Preliminary data indicate that of all active treatments, dawn simulation and bright light -- but not negative ions -- evoke circadian phase advances. It is hypothesized that: the magnitude of such advances will be positively correlated with the degree of clinical improvement, while high-density negative ions will be effective without evoking phase advances; both photic and nonphotic placebo controls will be less effective than the active treatments, and not evoke phase advances; and that dawn simulation and high-density ions will equal or surpass bright light in efficacy. A nonphotic treatment for SAD (negative ions) would offer an alternative to light for nonresponders and an adjunctive treatment for partial responders. Treatment during the final hours of sleep, an "automatic" procedure designed to increase patient acceptance and compliance in clinical practice, provides a major departure from post-awakening bright light therapy.

Institution: NEW YORK STATE PSYCHIATRIC INSTITUTE, 1051 RIVERSIDE DR, NEW YORK, NY 10032
Funding Agency: NATIONAL INSTITUTE OF MENTAL HEALTH
Investigator's Name: SZUBA, MARTIN P.

Project Title: SLEEP AND CHRONOBIOLOGY OF LATE-LIFE DEPRESSION

Abstract: The aims of this program include: 1) to support his development into an independent research scientist 2) to support and enhance the applicant's development as an investigator in sleep and chronobiology in the elderly; 3) to develop him for a faculty leadership role in mood disorders at Penn; and 4) to enhance the study of late-life mood disorders at Penn, using a chronobiologic approach. These aims will be structured around a four-part plan: 1) A program of formal academic courses and tutorials aimed at enhancing his research skills. 2) Research training, supervised by Drs. David Dinges and Ira Katz. This training will include supervised participation in three ongoing studies of the Center for Sleep and Respiratory Neurobiology and the Clinical Research Center (CRC) in Depression in the Aged: Medical- Psychiatric Co-Morbidity (I. Katz, PI). 3) Performance of a separate research project: The first systematic randomized, double-blind, placebo-controlled treatment trial of the effects of exogenous melatonin administration on sleep, mood, and circadian rhythms in depressed elderly subjects. The specific aims of the study include a thorough evaluation in elderly depressed subjects with insomnia of subjective, behavioral, and physiological indices of sleep, in the laboratory and at home, as well as recording of circadian physiology during an unmasking protocol (constant routine), prior to and following treatment with melatonin or placebo. 4)Preparation, as Principal Investigator, of an independent research grant application.

Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA 19104-6380
Department: PSYCHIATRY
Funding Agency: NATIONAL INSTITUTE ON AGING
Investigator's Name: EASTMAN, CHARMANE I.

Project Title: MELATONIN, HUMAN CIRCADIAN RHYTHMS, AND SLEEP

Abstract: Shift work effects millions of people and many experience serious health-related consequences, such as shortened and disrupted sleep, fatigue, impaired performance, and gastrointestinal disturbances. Night shift workers experience these symptoms because their internal circadian rhythms rarely phase shift to align with the new (daytime) sleep schedule. One reason it is so difficult for these individuals to shift is that they continue to be exposed to the natural 24-hour light-dark cycle, a very powerful zeitgeber that works to keep rhythms synchronized for alertness during the day and sleep at night. One strategy for shift work adaptation is to force the circadian pacemaker (clock) to phase shift to realign with shifted sleep-wake schedules, while another approach is to try to improve shift worker's daytime sleep and nighttime performance without shifting rhythms. Melatonin is a hormone normally secreted by the pineal gland at night. Previous studies suggest that exogenously-administered melatonin has phase-shifting as well as sedative effects. In Study 1, the investigator will determine whether appropriately-timed melatonin can phase shift the circadian pacemaker to align with a 9-hour shift of the sleep-wake schedule in subjects who do simulated night work and are exposed to the natural 24-hour light-dark cycle and other zeitgebers. Phase shifts will be assessed using phase measures derived from endogenous melatonin secretion and core body temperature. In Study 2, the investigator will investigate the immediate effects of two different doses of melatonin on daytime sleep after simulated night work, and assess the effects of melatonin treatment on nighttime performance. Sleep will be polygraphically-recorded to assess changes to sleep architecture, and multiple sleep latency tests and computerized performance tests will be performed during the night shifts to assess alertness.

Institution: RUSH-PRESBYTERIAN-ST LUKES MEDICAL CTR, 1653 W CONGRESS PKWY, CHICAGO, IL 60612
Funding Agency: NATIONAL INST OF NEUROLOGICAL DISORDERS AND STROKE
Investigator's Name: WEHR, THOMAS A.

Project Title: ROLE OF THE CIRCADIAN SYSTEM IN THE REGULATION OF HABITUAL SLEEP DURATION

Abstract: Habitual sleep duration varies greatly among individuals. The biological meaning of this variation is unknown, and so are the triggers for sleep and awakening. We proposed that the differences in sleep duration are not just a consequence of exogenous (e.g. social) factors, but result from differences in the endogenous circadian pacemaker. The circadian pacemaker, which is located in the suprachiasmatic nucleus of the hypothalamus, controls the timing of sleep and wakefulness, and regulates the circadian rhythms of a variety of physiological variables. We hypothesized that the internal biological night, as indicated by the nocturnal interval of active melatonin secretion, low body temperature, and increasing sleepiness is shorter in short sleepers than in long sleepers. Young (21-31 years) healthy male and female short sleepers (N=7; sleep duration <6 hours) and long sleepers (N=5; >9 hours) were selected on the basis of questionnaires, 2-4 week sleep logs and wrist motor activity recordings. Subjects underwent a ~40-hour constant routine protocol during which they stayed awake in bed in dim light, and without time cues. Fluids and isocaloric meals were given every hour and every 2 hours, respectively. The purpose of this protocol was to minimize or distribute evenly the masking influences of sleep, posture, exercise, meals, and light, which distort the endogenous circadian rhythms. Blood samples were taken every 30 minutes for 24 hours. Plasma melatonin was measured by radioimmunoassay. Body temperature was recorded continuously with a rectal probe. Sleepiness rating were obtained every 30 minutes on 100-mm visual analog scales. The duration of the nocturnal interval of detectable melatonin levels did not differ between groups. In contrast, the duration of the nocturnal trough in body temperature was shorter in the short sleepers than in the long sleepers (9.7+/-0.4 (SEM) vs. 11.8+/-1.1 hours; p<0.05, Wilcoxon), and so was the nocturnal interval of increasing sleepiness (8.9+/-0.3 vs. 10.5+/-0.8 hours; p<0.05). The peak in sleepiness coincided in both groups with habitual wake-up time, which occurs about 2.5 hours later in the long sleepers. The difference in the circadian rhythms of body temperature and sleepiness are consistent with our hypothesis. Previously, it has been shown that both body temperature and sleepiness are also directly affected by melatonin. Thus, if melatonin constitutes a circadian signal for sleep, the absence of differences in the duration of melatonin secretion may reflect differences in the sensitivity to this signal in short and long sleepers.)

Institution: NATIONAL INSTITUTE OF MENTAL HEALTH, BETHESDA, MD
Funding Agency: NATIONAL INSTITUTE OF MENTAL HEALTH
Investigator's Name: KRIPKE, DANIEL F.

Institution: UNIVERSITY OF CALIFORNIA SAN DIEGO, GILMAN & LA JOLLA VILLAGE DR, SAN DIEGO, CA 92093
Department: PSYCHIATRY
Funding Agency: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Investigator's Name: ROSENTHAL, N E.

Project Title: SEROTONERGIC ABNORMALITIES IN SEASONAL AFFECTIVE DISORDER AND LIGHT THERAPY

Abstract: Our prior research suggests that serotonergic mechanisms are involved in the pathophysiology of seasonal affective disorder (SAD) and the therapeutic action of light therapy. Given abnormal activation-euphoric responses to the serotonin agonist m-chlorophenylpiperazine (m-CPP) in patients with SAD, we tested the hypothesis that SAD patients would also exhibit abnormal cerebral metabolic responses to this drug, as measured by positron emission tomography (PET) scanning. Results confirmed previous findings of activation-euphoria in patients compared to controls following m-CPP administration. We found no global differences in cerebral metabolism in patients as compared to controls either at baseline or following the drug challenge. The possibility of regional cerebral metabolic differences in patients await future data analysis. In a second PET scan study we tested the hypotheses that (1) one hour of light therapy would tend to normalize the level of blood flow in limbic and paralimbic regions of the brain and exert no effect on controls and (2) the antidepressant response to light therapy following one hour of exposure will correlate with the antidepressant response after one and two weeks of light patients remitted on light therapy underwent independent depletions of serotonin and catecholamines. Serotonin and catecholamines were depleted with a tryptophan-free amino acid beverage (plus amino acid capsules) and the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine. Both depletion procedures, compared to sham depletion, equally reversed the antidepressant effects of light therapy. In ongoing studies of lymphoblastoid cell lines, we have attempted to find abnormal polymorphisms in genes related to serotonergic functioning in SAD patients. We have found that the short allele of the 5-HT transporter-linked polymorphism (5-HTTLPR) is associated with SAD, as well as with greater levels of seasonality (seasonally-related behavioral changes such as mood, energy, appetite) in patients with SAD.

Institution: NATIONAL INSTITUTE OF MENTAL HEALTH, BETHESDA, MD
Funding Agency: NATIONAL INSTITUTE OF MENTAL HEALTH
Investigator's Name: CAMPBELL, SCOTT S.

Project Title: EXTRAOCULAR CIRCADIAN PHOTOTRANSDUCTION IN HUMANS

Abstract: Circadian rhythm sleep disorders and seasonal affective disorder affect a large number of individuals across a wide age range. Timed exposure to bright light shows promise as an effective treatment for alleviation of such sleep and mood disorders which are thought to involve the biological timing system. Yet, light treatment as currently practiced has significant drawbacks in terms of user compliance and efficacious timing of administration. The time-consuming and tedious nature of most light treatment regimens make them difficult for many people to use on a consistent and continuing basis. Moreover, the nature of the endogenous clock's response to light dictates that maximum effects are obtained at times when people are typically asleep. We have shown that the human circadian clock responds to extraocular light exposure in a manner similar to that when light is presented to the eyes. This finding of extraocular circadian clock resetting in humans offers potentially exciting solutions to the problems currently complicating the therapeutic use of bright light. By eliminating the need to receive light via the retinae, light delivery systems can be made more easily portable, and therefore, less intrusive on users' behavior. Perhaps more importantly, by eliminating the need to receive light through the eyes, treatment regimens conceivably may be implemented even while patients are asleep, thus enhancing ease of use and taking advantage of the most optimal times of light administration. Yet, before treatment approaches and regimens can be successfully developed and implemented using extraocular sites, it is important to confirm and expand our original findings. This project will take two important steps in this regard: First, we propose to replicate our original study using a larger study sample and more suitable controls. Secondly, it is proposed to characterize the phase response of the circadian clock to extraocular light presented during sleep. In two laboratory-based studies, both using a counter-balanced design, we will examine relevant circadian parameters in a total of 72 healthy young adults during baseline, active and control conditions. These studies address issues crucial to the successful development and implementation of light treatments using extraocular exposure, and they form the basis for a more complete understanding of the role of light in human circadian physiology.

Institution: WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY, NEW YORK, NY 10021
Department: PSYCHIATRY
Funding Agency: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Investigator's Name: LEIBENLUFT, ELLEN

Project Title: CIRCADIAN INTERVENTIONS IN PATIENTS WITH RAPID-CYCLING BIPOLAR DISORDER

Abstract: Patients with rapid cycling bipolar disorder (RCBD) experience at least four episodes of mania, hypomania, and/or depression in a year. They suffer significant morbidity and are frequently resistant to conventional treatments. An unstable sleep/wake cycle is both characteristic of the illness and feeds back on the symptoms so as to exacerbate them. In this series of projects, we are exploring whether interventions designed to stabilize the sleep-wake and circadian systems have mood-stabilizing effects in patients with RCBD. We have previously demonstrated that extended scotoperiod may have mood- stabilizing effects. Pilot data also indicated that midday bright light might have mood-stabilizing effects, while morning phototherapy might destabilize mood in patients with RCBD. The possible mood-stabilizing effects of midday phototherapy are now being tested in a controlled clinical trial of midday bright light vs. negative ion generator. Nine patients have completed the phototherapy trial, and more are being recruited.

Institution: NATIONAL INSTITUTE OF MENTAL HEALTH, BETHESDA, MD
Fiscal Year: 1999
Funding Agency: NATIONAL INSTITUTE OF MENTAL HEALTH
Investigator's Name: SHARKEY, KATHERINE M.

Project Title: PHASE SHIFTING AND SEDATIVE EFFECTS OF MELATONIN

Abstract: This research plan describes two studies that test different properties of the neurohormone melatonin in humans undergoing a large shift in their sleep-wake schedule. The first is a field study to determine whether appropriately-timed melatonin administration can help shift the internal circadian pacemaker to adjust to a 9-hr shift in the sleep-wake schedule. In this protocol, 48 subjects will undergo a 9-hr advance or delay in their sleep-wake schedule for 8 days. Subjects will be randomly assigned to take placebo or melatonin on the first 4 days of the shifted schedule. Phase will be measured using continuous recording of core body temperature. In the second study, we will test melatonin's efficacy in improving sleep during the day after night work without shifting endogenous circadian phase. Subjects (N=10) will each participate in a melatonin trial and a placebo trial. After a week of baseline sleep, subjects will come to the lab for 2 nights of simulated night work followed by daytime sleep. Sleep will be polysomnographically-recorded on 2 baseline nights, 2 day sleep episodes, and l recovery night. In addition, subjects will undergo Multiple Sleep Latency Tests and performance tests during the night work episodes.

Institution: RUSH UNIVERSITY, 600 S PAULINA ST, CHICAGO, IL 60612
Department: PSYCHOLOGY AND SOCIAL SCIENCES
Funding Agency: NATIONAL INSTITUTE OF MENTAL HEALTH
Investigator's Name: SACK, ROBERT L.

Project Title: MELATONIN FOR CIRCADIAN SLEEP DISORDERS IN THE BLIND

Abstract: Totally blind people have sleep problems that are caused by desynchronized circadian rhythms. Without photic time cues, the internal body clock tends to "free-run" on about a 24.5 cycle; as a result, circadian rhythms move in and out of phase with desired sleep times, causing recurrent insomnia and impaired daytime alertness. Melatonin has been designated as an orphan drug for the treatment of circadian rhythm sleep disorders in blind people with no light perception. Nightly oral administration of melatonin may act as a "darkness signal" that can synchronize internal rhythms to desired sleep times. In addition to this "clock resetting" (phase shifting) action, melatonin may benefit insomnia in blind patients by a direct sleep-promoting (sedative) action.

Institution: OREGON HEALTH SCIENCES UNIVERSITY, 3181 SW SAM JACKSON PARK RD, PORTLAND, OR 97201
Department: PSYCHIATRY
Funding Agency: NATIONAL CENTER FOR RESEARCH RESOURCES
Investigator's Name: SACK, ROBERT L.

Project Title: PHASE SHIFTING EFFECTS OF MELATONIN IN SIGHTED AND BLIND SUBJECTS

Abstract: The purpose of this study is to find the optimum timing, dose and duration of melatonin administration for phase advancing (shifting to an earlier time)the endogenous melatonin rhythms, which may occur in winter depression and delayed sleep phase syndrome and may lead to symptoms of insomnia, lack of energy and depression. The phase-advancing effects of melatonin may be useful for treating such disorders.

Project Title: SHIFTING CIRCADIAN RHYTHMS WITH BRIGHT LIGHT

Abstract: Night shift workers suffer from poor sleep, fatigue, gastrointestinal disturbances, and impaired performance. Other consequences are diminished job and public safety. Most of these problems are due to the face that the endogenous circadian clock of the worker does not phase shift to adjust to the night work and day sleep schedule. The 24-hr time cues of the world, such as the natural light-dark cycle, keep the clock from phase shifting. We plan to continue basis research on the use of high intensity "bright" light to phase shift the circadian clock. The protocols are set up to mimic night shift work, so that the results will be more directly applicable to shift work. Subjects stay awake during several 8-hr night shifts, and are exposed to various patterns of bright light during the night shifts. They live at home and go to sleep during the daytime after the night shifts. Thus, they are exposed to the same conflicting time cues as read shift workers. In this sense these are field studies as opposed to laboratory studies in which subjects are shielded from the natural light-dark cycle. In all studies, the circadian rhythm of body temperature is used as a marker for the phase of the circadian clock, photosensors measure light exposure, and questionnaires provide estimates of sleep duration, fatigue and mood. We propose five studies. 1) A study comparing different patterns of bright light (moving and stationary) to determine which are better for phase shifting circadian rhythms. 2) A study of whether medium intensity light can be used to phase shift circadian rhythms. 3) A study of whether bright light occurring at the wrong time during the night shift can keep the rhythms from phase shifting. 4) A study of whether adjustment to the night shift produced by bright light will interfere with subsequent adaptation back to the day shift. 5) A study of whether exercise changes the phase shifting effects of bright light and whether exercise alone can be used to phase shift rhythms.

Institution: RUSH-PRESBYTERIAN-ST LUKES MEDICAL CTR, 1653 W CONGRESS PKWY, CHICAGO, IL 60612
Funding Agency: NATIONAL INST OF NEUROLOGICAL DISORDERS AND STROKE
Investigator's Name: MONK, TIMOTHY H.

Project Title: PHASE SHIFT TOLERANCE IN OLDER PEOPLE

Abstract: This project is concerned with the neuroscience of aging, and in particular with the response of the aging human circadian timekeeping system (CTS) to an abrupt shift in routine. The project will assess the adjustment of sleep, circadian rhythms, mood and performance in healthy elderly (55-90y) people to an acute (6h) phase delay in routine. This will allow the test of hypotheses regarding how well older people can cope with delays in routine that are often required either to remedy advanced sleep phase syndrome (ASPS) in which seniors have pathologically early bedtimes and waketimes, or to cope with evening- and night-working schedules which require sleep periods to be delayed by several hours. Knowledge of the aging circadian system's ability to phase delay and its effects on sleep, alertness, mood and performance is also of general interest. In all seniors, these entrainment processes are at work, ensuring that the CTS retains an appropriate temporal orientation, and a period length of exactly 24h, thus avoiding the episodic disruptions in sleep and daytime functioning that occur when the GTS runs at non-24h periods (as occurs, for example, in the profoundly blind). Fifteen-day experiments will be conducted in a controlled temporal environment in which the only time cues come from the experimenter. Thirty seniors, 15 younger seniors (55-70y) and 15 older seniors (71-90y) will each experience a surreptitious 6h phase delay in routine accomplished by "stretching" the waking part of day #6 by 6h, and holding each event thereafter (bedtimes, waketimes, meals, etc.) to a 6h phase delayed position (e.g., bedtimes at 0400 rather than 2200). Circadian rectal temperature rhythms (sampled every minute around the clock) will be used to track the adjustment of the CTS to the phase shift. All sleeps will polygraphically recorded, and mood, subjective activation, and performance assessed seven times per day. The phase delay condition studied in this project will be compared with a phase advance condition studied in 25 older seniors (71 -91 y) in an earlier experiment by the P.I. funded by the National Institute on Aging. The following specific hypotheses will be tested: 1) The GTS of seniors will adjust more slowly to phase delays than to phase advances; 2) this directional asymmetry will be more marked in older seniors than in younger seniors; 3) the phase shift will result in more disruptions in sleep and in daytime mood, alertness and performance in older seniors than in younger seniors.

Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, 4200 5TH AVE, PITTSBURGH, PA 15260
Department: PSYCHIATRY
Funding Agency: NATIONAL INSTITUTE ON AGING
Investigator's Name: ZEE, PHYLLIS C.

Project Title: MANIPULATIONS OF EXTERNAL ZEITGEBERS IN THE ELDERLY

Abstract: Sleep disturbances are common among older persons. Exposure to synchronizing agents for athe circadian system (zeitgebers) such as bright light, social cues and physical activity are greatly diminished in old age. This is particularly true for the institutionalized elderly and may contribute to the constellation of sleep/wake cycle and behavioral disorders which are frequently seen in this group. Preliminary studies indicate that enforcement of photic and non-photic zeitgebers results in alterations of circadian rhythmicity and sleep with associated improvements in daytime function in elderly residents of assisted facilities. The specific aims of the present project are: 1) To test the hypothesis that the timing of bright light/dark or social/physical activity schedules is critical to their efficacy to alter circadian rhythms and sleep, as well as to improve daytime alertness and performance, 2) To test the hypothesis that enforcement of a social schedule without a concomitant increase in physical activity will improve daytime function and nocturnal sleep, and 3) To test the hypothesis that reinforcement of sleep homeostatic mechanisms by enhancement of slow wave sleep will increase alertness and measures of performance. Older residents of assisted living and retirement facilities will be studies before, during and after a 14 day period of intervention will either morning or evening bright light, or structured social and physical exercise; social activity alone or combined social and physical activity programs; or pharmacological treatment to enhance slow wave sleep. Rest-activity cycles and light exposure will be monitored continuously throughout each protocol. Circadian profiles of temperature and heart rate, tests of neuropsychological performance, recording of nocturnal sleep, and measurement of melatonin and cortisol levels in saliva will be determined before, during and after athe various treatments. The results from these studies will determine the extent to which photic and non-photic zeitgebers can be used to alter circadian rhythmicity, improve sleep, alertness and performance in the elderly, as well as to provide essential practical information for th application of these types of intervention in the "real world" setting.

Institution: UNIVERSITY OF CHICAGO, 5801 S ELLIS AVE, CHICAGO, IL 60637
Department: MEDICINE
Funding Agency: NATIONAL INSTITUTE ON AGING
Investigator's Name: BRANDON, DEBRA H.

Project Title: CYCLED LIGHT VERSUS NEAR DARKNESS IN THE PRETERM INFANT

Abstract: Light affects physiologic parameters, physical growth, sleep-wake states, day/night cycling, and sensory systems of preterm infants. This study will examine the effects of cycled light and continuous near darkness on the growth and development of preterm infants, who will be followed from the time of admission into the neonatal intensive care nursery until term or hospital discharge. Preterm infants less than 31 weeks gestation admitted to a Southeastern regional tertiary care teaching hospital will be eligible for participation. Infants will be randomly assigned to one of 3 groups: Group 1 will receive continuous near darkness from birth until 32 weeks gestation with subsequent cycled light, Group 2 will receive cycled light from birth, and Group 3 will receive continuous near darkness from birth. Outcome measures will include physical growth (height, weight, head circumference), length of hospital stay, number of ventilator days, sleep-wake state organization, day/night organization of physiologic parameters (e.g. heart rate) and neurobehavioral organization (e.g. visual and auditory functioning). The findings are expected to indicate the most appropriate timing of cycled light.