Assistant Professor, Psychiatry & Behavioral Science - Stanford/VA Aging Clinical Research Center
PhD, Harvard University, Neurobiology (1999)
AB, Vassar College, Biology (1993)
Dr. Zeitzer's research examines non-image forming light perception. Basically, everything that the eye does with light except what is thought of as "vision". He examines the manner in which humans respond to light and ways to manipulate this responsiveness. His work has direct application in jet lag, shift work, and altered sleep timing in teens and older individuals.
Recent research provides evidence that disrupted circadian rhythms, including hormonal patterns and sleep, are associated with increased risk of breast cancer incidence and faster progression to mortality. We have observed that a loss of normal diurnal cortisol rhythm associated with more awakenings during the night predicts early mortality with metastatic breast cancer. Other recent studies have shown that nighttime shift work is associated with higher breast cancer incidence, and in a murine model disrupting circadian cortisol cycles produced a doubling of implanted tumor growth. There is also recent evidence that abnormal clock genes are associated with cancer. However, it is not clear whether sleep disruption per se affects breast cancer progression, or whether such an effect is mediated by hormonal and immune dysregulation of this prevalent and hormone-mediated cancer. We propose to study sleep disruption as a prognostic factor in the progression of metastatic breast cancer. We will also examine sleep patterns in association with disrupted circadian rhythms of cortisol, ACTH, and melatonin as well as measures of immune function known to be salient to breast cancer progression. These are natural killer cell cytoxicity and specific cytokine, IL-6. We plan to recruit 105 women 45 years through 75 years with metastatic or recurrent breast cancer and 20 age and SES-matched controls for a two-week at home sleep study with Actiwatch and two nights of in-home EEG monitoring, followed by 28 hours of continuous blood sampling and one night of EEG sleep monitoring in our lab at Stanford. This will provide a full examination of circadian hormones associated with sleep patterns. We will relate these assessments to the subsequent course of breast cancer progression. Results of this study will provide specific evidence regarding how improved sleep management may affect the course of breast cancer. Aim 1: To study 24-hr diurnal rhythms of HPA axis hormones and melatonin in women with metastatic or recurrent breast cancer. Hypothesis 1: Women with metastatic or recurrent breast cancer will have reduced amplitude and disrupted phase of 24-hr diurnal rhythms of cortisol, ACTH, and melatonin. Aim 2: To describe sleep disruption in women with metastatic breast cancer and examine psychosocial, endocrine, and immune factors that may be associated with sleep disruption. Hypothesis 2: Women with metastatic or recurrent breast cancer will have a higher incidence of both at home and laboratory-examined sleep disruption than control women without breast cancer. Hypothesis 3: Poorer sleep quality will be associated with more pain, more emotional suppression in response to stressors, less emotional support, greater depression and anxiety, and greater perceived and traumatic stress. Hypothesis 4: Poorer sleep quality and quantity of sleep and daytime sleepiness and fatigue will be associated with abnormal circadian neuroendocrine (i.e., cortisol, ACTH, and melatonin) and immune patterns (i.e., suppressed day and night time NK activity and loss of NK rhythms; increased day time IL-6 levels and /or loss of IL-6 rhythm). Aim 3: To study the relationship between sleep disruption and survival time among metastatic and recurrent breast cancer patients. Hypothesis 5: Poorer sleep quality and quantity of sleep will predict shorter survival. Hypothesis 6: Reduced diurnal amplitude and an abnormal phase of cortisol will predict shorter survival. Explanatory Aim 4: To investigate whether sleep disruption mediates the relation of psychosocial factors to health outcomes.
Stanford is currently not accepting patients for this trial. For more information, please contact Bita Nouriani, (650) 723 - 8479.
Modafinil, trade named Provigil, is a medication approved by the Food and Drug Administration for the treatment of narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. Each of these problems is characterized by difficulty sleeping at night and excessive daytime sleepiness. Modafinil is prescribed during the day to counteract this sleepiness. The idea behind this treatment is that sleepiness that leads to napping during the day prevents a patient from being tired or sleepy enough to get good sleep at night. This study is designed to determine if the medication can "reset" participants' sleep/wake rhythm to a more normal rhythm.
Stanford is currently not accepting patients for this trial. For more information, please contact Ban Ku, (650) 849 - 1971.
The proposed study will recruit 60 women with breast cancer who finished undergoing treatment who complain of persistent insomnia problems that began with onset of their cancer diagnosis. The eligible women would be randomized and stratified by sleep problems to two arms: (Acupuncture Arm vs. Sham Acupuncture) with a goal of having 48 patients complete the study (we anticipate about 20% attrition rate). The study interventions will begin after patients completed their treatment. The placebo control for acupuncture will be a validated sham acupuncture control Assessments will be made with daily diaries and with weekly questionnaires. PSG data will be collected on the subsample of the population. Data will be gathered via pencil-and-paper measures before, during, immediately following, one month following the completion of treatment and six months after the conclusion of treatment. In addition, actigraphy data (objective sleep continuity data) will be acquired prior to and following treatment
Stanford is currently not accepting patients for this trial. For more information, please contact David Spiegel, (650) 723 - 6421.
To examine the change in balance that occurs in older individuals when exposed to different colored lights at night.
Stanford is currently not accepting patients for this trial. For more information, please contact Jamie M Zeitzer, PhD, 650-493-5000 Ext. 62410.
The purpose of this study is to determine if replacing melatonin function with a melatonin agonist (ramelteon) in individuals that lack endogenous melatonin production (tetraplegia) helps to alleviate self-reported sleep disruption.
Stanford is currently not accepting patients for this trial. For more information, please contact Ban Ku, (650) 849 - 1971.
Delayed Sleep Phase Disorder (DSPD) is a sleep disruption that commonly occurs in teens and manifests as a difficulty in waking up in the morning, going to sleep early enough at night, and daytime disturbances such as depression, fatigue, and restlessness. The purpose of this study is to determine if brief flashes of light, that are scheduled to occur during sleep, are effective in treating DSPD.
The purpose of this study is to evaluate the efficacy and safety of a six month double-mask treatment of tasimelteon or placebo in male and female subjects with Non-24-Hour Sleep-Wake Disorder
Light exerts a direct effect on sleep and wakefulness in nocturnal and diurnal animals, with a light pulse during the dark phase suppressing locomotor activity and promoting sleep in the former. In the present study, we investigated this direct effect of light on various sleep parameters by exposing mice to a broad range of illuminances (0.2-200 ?W/cm(2) ; equivalent to 1-1000 lux) for 1 h during the dark phase (zeitgeber time 13-14). Fitting the data with a three-parameter log model indicated that ?0.1 ?W/cm(2) can generate half the sleep response observed at 200 ?W/cm(2) . We observed decreases in total sleep time during the 1 h following the end of the light pulse. Light reduced the latency to sleep from ~30 min in darkness (baseline) to ~10 min at the highest intensity, although this effect was invariant across the light intensities used. We then assessed the role of melanopsin during the rapid transition from wakefulness to sleep at the onset of a light pulse and the maintenance of sleep with a 6-h 20 ?W/cm(2) light pulse. Even though the melanopsin knockout mice had robust induction of sleep (~35 min) during the first hour of the pulse, it was not maintained. Total sleep decreased by almost 65% by the third hour in comparison with the first hour of the pulse in mice lacking melanopsin, whereas only an 8% decrease was observed in wild-type mice. Collectively, our findings highlight the selective effects of light on murine sleep, and suggest that melanopsin-based photoreception is primarily involved in sustaining light-induced sleep.
View details for DOI 10.1111/ejn.12189
View details for PubMedID 23510299
To determine if there is a specific pattern of gross motor activity associated with apathy in individuals with Alzheimer disease (AD).Examination of ad libitum 24-hour ambulatory gross motor activity patterns.Community-dwelling, outpatient.Ninety-two individuals with AD, 35 of whom had apathy.Wrist actigraphy data were collected and examined using functional principal component analysis (fPCA).Individuals with apathy have a different pattern of gross motor activity than those without apathy (first fPCA component, p <0.0001, t = 5.73, df = 90, t test) such that there is a pronounced decline in early afternoon activity in those with apathy. This change in activity is independent of depression (p = 0.68, F[1, 89] = 0.05, analysis of variance). The decline in activity is consistent with an increase in napping. Those with apathy also have an early wake and bedtime (second fPCA component, t = 2.53, df = 90, p <0.05, t test).There is a signature activity pattern in individuals with apathy and AD that is distinct from those without apathy and those with depression. Actigraphy may be a useful adjunctive measurement in the clinical diagnosis of apathy in the context of AD.
View details for DOI 10.1016/j.jagp.2012.12.012
View details for PubMedID 23498386
To determine the impact of nocturia on objective measures of sleep in older individuals with insomnia.The sleep and toileting patterns of a group of community-dwelling older men (n = 55, aged 64.3 ± 7.52 years) and women (n = 92, aged 62.5 ± 6.73 years) with insomnia were studied for two weeks using sleep logs and one week using actigraphy. The relationships between nocturia and various sleep parameters were analyzed with ANOVA and linear regression.More than half (54.2% ± 39.9%) of all log-reported nocturnal awakenings were associated with nocturia. A greater number of trips to the toilet was associated with worse log-reported restedness (p < 0.01) and sleep efficiency (p < 0.001), as well as increases in actigraph-derived measures of the number and length of nocturnal wake bouts (p < 0.001) and wake after sleep onset (p < 0.001). Actigraph-determined wake bouts were 11.5% ± 23.5% longer on nights on which there was a trip to the toilet and wake after sleep onset was 20.8% ± 33.0% longer during these nights.Nocturia is a common occurrence in older individuals with insomnia and is significantly associated with increased nocturnal wakefulness and decreased subjective restedness after sleep.
View details for DOI 10.5664/jcsm.2492
View details for Web of Science ID 000316209800010
View details for PubMedID 23493881
The present work aimed to extend models suggesting that obstructive sleep apnea (OSA) is associated with worse cognitive performance in community-dwelling older adults. We hypothesized that in addition to indices of OSA severity, hypertension is associated with worse cognitive performance in such adults.The PTSD Apnea Clinical Study recruited 120 community-dwelling, male veterans diagnosed with PTSD, ages 55 and older. The Rey Auditory Verbal Learning Test (RAVLT) and Color-Word Interference Test (CWIT) were measures of auditory verbal memory and executive function, respectively. Apnea-hypopnea index (AHI), minimum and mean pulse oximeter oxygen saturation (min SpO(2), mean SpO(2)) indicators were determined during standard overnight polysomnography. Multivariate linear regression and receiver operating characteristic (ROC) curve analyses were performed.In regression models, AHI (??=?-4.099; p?0.01) and hypertension (??=?-4.500; p?0.05) predicted RAVLT; hypertension alone (??=?9.146; p?0.01) predicted CWIT. ROC analyses selected min SpO(2) cut-points of 85% for RAVLT (??=?0.27; ?²?=?8.23, p?0.01) and 80% for CWIT (??=?0.25; ?²?=?12.65, p?0.01). Min SpO(2) cut-points and hypertension were significant when added simultaneously in a regression model for RAVLT (min SpO(2), ??=?4.452; p?0.05; hypertension, ??=?-4.332; p?0.05), and in separate models for CWIT (min SpO(2), ??=?-8.286; p?0.05; hypertension, ??=?-8.993; p?0.01).OSA severity and presence of self-reported hypertension are associated with poor auditory verbal memory and executive function in older adults.
View details for DOI 10.1007/s11325-011-0632-8
View details for Web of Science ID 000311301700038
View details for PubMedID 22193972
Across all stages of Alzheimer disease (AD), apathy is the most common neuropsychiatric symptom. Studies using the Neuropsychiatric Inventory (NPI) have found that apathy is present in up to 70% of individuals with Alzheimer disease. One of the main difficulties in assessing apathy and other neuropsychiatric symptoms is the absence of reliable, objective measures. Motor activity assessment using ambulatory actigraphy could provide an indirect, objective evaluation of apathy. The aim of our study was to assess the relationship between apathy and daytime motor activity in AD, using ambulatory actigraphy.One hundred seven AD outpatients wore a wrist actigraph (Motionlogger) during seven consecutive 24-hour periods to evaluate motor activity. Participants were divided into two subgroups according to their apathy subscores on the NPI: individuals with apathy (NPI-apathy subscores >4) and those without. Daytime mean motor activity scores were compared between the two subgroups.Individuals with AD who had symptoms of apathy (n = 43; age = 79 ± 4.7 years; Mini-Mental State Examination = 20.9 ± 4.8) had significantly lower daytime mean motor activity than AD patients without apathy (n = 64; age = 76.3 ± 7.7; Mini-Mental State Examination = 21.5 ± 4.7), while nighttime mean motor activity did not significantly differ between the two subgroups.Ambulatory actigraphy could be added to currently used questionnaires as a simple, objective technique for assessing apathy in the routine assessment of AD patients.
View details for DOI 10.1097/JGP.0b013e31823038af
View details for Web of Science ID 000308078500010
View details for PubMedID 21997602
Scheduled exposure to bright light (phototherapy) has been used, with varying degrees of success, to treat sleep disruption in older individuals. Most of these studies have been done in institutional settings and have used several hours of daily light exposure. Such a regimen in the home setting may be untenable, especially when the individual with the sleep disruption has memory impairment and is being cared for by a family member. As such, we examined the effectiveness of a "user-friendly" phototherapy protocol that would be readily usable in the home environment.We exposed a group of 54 older caregiver/care recipient dyads, in which the care recipient had memory impairment, to two weeks of morning bright light phototherapy. Dyads were exposed to either bright white (?4200 lux) or dim red (?90 lux) light for 30 min every day, starting within 30 min of rising. All subjects also received sleep hygiene therapy. Objective (actigraphy) and subjective measures of sleep and mood were obtained at baseline and at the end of the two weeks of phototherapy.In care recipients, actigraphy- and log-determined time in bed and total sleep time declined in the active condition (p<0.05, ANOVA); there was no corresponding change in subjective insomnia symptoms (p's>0.37, ANOVA). The decrease in the time in bed was associated with an earlier out of bed time in the morning (p<0.001, Pearson correlation). The decrease in the total sleep time was associated with a decrease in sleep efficiency (p<0.001, Pearson correlation) and an increase in wake after sleep onset (p<0.001, Pearson correlation). In caregivers, there were no differential changes in actigraphic measures of sleep (p's>0.05, ANOVA). Actigraphy-measured wake after sleep onset and sleep efficiency did, however, improve in both conditions, as did sleepiness, insomnia symptoms, and depressive symptomatology (p's<0.05, ANOVA).Exposure to this regimen of phototherapy diminished sleep in older individuals with memory impairments. Their caregivers, however, experienced an improvement in sleep and mood that appeared independent of the phototherapy and likely due to participation in this protocol or the sleep hygiene therapy.
View details for DOI 10.1016/j.sleep.2011.11.013
View details for Web of Science ID 000303346800016
View details for PubMedID 22406033
Central nervous system (CNS) histamine is low in individuals with narcolepsy, a disease characterized by severe fragmentation of both sleep and wake. We have developed a primate model, the squirrel monkey, with which we can examine the role of the CNS in the wake-consolidation process, as these primates are day-active, have consolidated wake and sleep and have cerebrospinal fluid (CSF) that is readily accessible. Using this model and three distinct protocols, we report herein on the role of CNS histamine in the wake consolidation process. CSF histamine has a robust daily rhythm, with a mean of 24.9?±?3.29?pg?mL(-1) , amplitude of 31.7?±?6.46?pg?mL(-1) and a peak at 17:49?± 70.3?min (lights on 07:00-19:00?hours). These levels are not significantly affected by increases (up to 161?±?40.4% of baseline) or decreases (up to 17.2?±?2.50% of baseline) in locomotion. In direct contrast to the effects of sleep deprivation in non-wake-consolidating mammals, in whom CSF histamine increases, pharmacologically induced sleep (?-hydroxybutyrate) and wake (modafinil) have no direct effects on CSF histamine concentrations. These data indicate that the time-course of histamine in CSF in the wake-consolidated squirrel monkey is robust against variation in activity and sleep and wake-promoting pharmacological compounds, and may indicate that histamine physiology plays a role in wake-consolidation such as is present in the squirrel monkey and humans.
View details for DOI 10.1111/j.1365-2869.2011.00957.x
View details for Web of Science ID 000301931500010
View details for PubMedID 21910776
To examine the validity of a novel caffeine intake questionnaire and to examine the effects of caffeine on sleep in college students.One-week, ad libitum behavior of 50 university students (28 female, 22 male; aged 20.9 ± 1.78 years) was examined with sleep logs, wrist actigraphy, and a novel daily questionnaire assessing caffeine intake at different times of day. Saliva samples were collected for caffeine assessment (questionnaire validation) and DNA extraction, and for analysis of a single nucleotide polymorphism in the adenosine receptor 2A (ADORA2A) gene.The caffeine questionnaire was able to accurately predict salivary concentrations of caffeine (R(2) = 0.41, P<0.001). Estimations of integrated salivary caffeine concentration during sleep were correlated with wake after sleep onset (WASO) most strongly in morning-type individuals (R(2) = 0.49; P<0.001, ANOVA), less so in intermediate chronotypes (R(2) = 0.16; P<0.001, ANOVA), and not significantly in evening-types (R(2) = 0.00098; P = 0.13, ANOVA). Using multivariate modeling methods we found that the ADORA2A genotype did not moderate the effects of caffeine on WASO, but did independently alter WASO such that those with the CC genotype had nearly three-times as much WASO as those with CT or TT.Our questionnaire was able to accurately predict salivary caffeine concentrations and helped to describe a novel relationship between the effects of caffeine on sleep and genotype and chronotype.
View details for DOI 10.1016/j.sleep.2011.11.011
View details for Web of Science ID 000303346300007
View details for PubMedID 22333316
OBJECTIVES:: To determine if there is a specific pattern of gross motor activity associated with apathy in individuals with Alzheimer disease (AD). DESIGN:: Examination of ad libitum 24-hour ambulatory gross motor activity patterns. SETTING:: Community-dwelling, outpatient. PARTICIPANTS:: Ninety-two individuals with AD, 35 of whom had apathy. MEASUREMENTS:: Wrist actigraphy data were collected and examined using functional principal component analysis (fPCA). RESULTS:: Individuals with apathy have a different pattern of gross motor activity than those without apathy (first fPCA component, p <0.0001, t = 5.73, df = 90, t test) such that there is a pronounced decline in early afternoon activity in those with apathy. This change in activity is independent of depression (p = 0.68, F[1, 89] = 0.05, analysis of variance). The decline in activity is consistent with an increase in napping. Those with apathy also have an early wake and bedtime (second fPCA component, t = 2.53, df = 90, p <0.05, t test). CONCLUSIONS:: There is a signature activity pattern in individuals with apathy and AD that is distinct from those without apathy and those with depression. Actigraphy may be a useful adjunctive measurement in the clinical diagnosis of apathy in the context of AD.
View details for PubMedID 22367164
To examine the effect of ambulatory daytime light exposure on phase delays and on the advances produced by timed exposure to bright evening or morning light.As a subset of a larger study, 32 older (63.0 ± 6.43 years) adults with primary insomnia were randomized to an at-home, single-blind, 12-week, parallel-group study entailing daily exposure to 45 min of scheduled evening or morning bright (?4000 lux) light. Light exposure patterns during the baseline and the last week of treatment were monitored using actigraphs with built-in illuminance detectors. Circadian phase was determined through analysis of in-laboratory collected plasma melatonin.Less daytime light exposure during the last week of treatment was significantly associated with larger phase delays in response to evening light (r's>0.78). Less daytime light exposure during the last week of treatment was also associated with a significant delay in wake time (r's>-0.75). There were no such relationships between light exposure history and phase advances in response to morning light.Greater light exposure during the daytime may decrease the ability of evening light, but not morning light, exposure to engender meaningful changes of circadian phase.
View details for DOI 10.1016/j.sleep.2011.02.005
View details for Web of Science ID 000295764800013
View details for PubMedID 21855408
The polymorphic variation in the val158met position of the catechol-O-methyltransferase (COMT) gene is associated with differences in executive performance, processing speed, and attention. The purpose of this study is: (1) replicate previous COMT val158met findings on cognitive performance; (2) determine whether COMT val158met effects extend to a real-world task, aircraft navigation performance in a flight simulator; and (3) determine if aviation expertise moderates any effect of COMT val158met status on flight simulator performance. One hundred seventy two pilots aged 41-69 years, who varied in level of aviation training and experience, completed flight simulator, cognitive, and genetic assessments. Results indicate that although no COMT effect was found for an overall measure of flight performance, a positive effect of the met allele was detected for two aspects of cognitive ability: executive functioning and working memory performance. Pilots with the met/met genotype benefited more from increased levels of expertise than other participants on a traffic avoidance measure, which is a component of flight simulator performance. These preliminary results indicate that COMT val158met polymorphic variation can affect a real-world task.
View details for DOI 10.1007/s10519-010-9436-z
View details for Web of Science ID 000294297200008
View details for PubMedID 21193954
Ocular light sensitivity is the primary mechanism by which the central circadian clock, located in the suprachiasmatic nucleus (SCN), remains synchronized with the external geophysical day. This process is dependent on both the intensity and timing of the light exposure. Little is known about the impact of the duration of light exposure on the synchronization process in humans. In vitro and behavioral data, however, indicate the circadian clock in rodents can respond to sequences of millisecond light flashes. In a cross-over design, we tested the capacity of humans (n?=?7) to respond to a sequence of 60 2-msec pulses of moderately bright light (473 lux) given over an hour during the night. Compared to a control dark exposure, after which there was a 3.5±7.3 min circadian phase delay, the millisecond light flashes delayed the circadian clock by 45±13 min (p<0.01). These light flashes also concomitantly increased subjective and objective alertness while suppressing delta and sigma activity (p<0.05) in the electroencephalogram (EEG). Our data indicate that phase shifting of the human circadian clock and immediate alerting effects can be observed in response to brief flashes of light. These data are consistent with the hypothesis that the circadian system can temporally integrate extraordinarily brief light exposures.
View details for DOI 10.1371/journal.pone.0022078
View details for Web of Science ID 000292657200045
View details for PubMedID 21760955
The goal of the study was to improve prediction of longitudinal flight simulator performance by studying cognitive factors that may moderate the influence of chronological age.We examined age-related change in aviation performance in aircraft pilots in relation to baseline cognitive ability measures and aviation expertise. Participants were aircraft pilots (N = 276) aged 40-77.9. Flight simulator performance and cognition were tested yearly; there were an average of 4.3 (± 2.7; range 1-13) data points per participant. Each participant was classified into one of the three levels of aviation expertise based on Federal Aviation Administration pilot proficiency ratings: least, moderate, or high expertise.Addition of measures of cognitive processing speed and executive function to a model of age-related change in aviation performance significantly improved the model. Processing speed and executive function performance interacted such that the slowest rate of decline in flight simulator performance was found in aviators with the highest scores on tests of these abilities. Expertise was beneficial to pilots across the age range studied; however, expertise did not show evidence of reducing the effect of age.These data suggest that longitudinal performance on an important real-world activity can be predicted by initial assessment of relevant cognitive abilities.
View details for DOI 10.1093/geronb/gbr031
View details for Web of Science ID 000293251900007
View details for PubMedID 21586627
One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes.One week of ad libitum ambulatory sleep data collection.At-home collection of sleep data and in-laboratory questionnaire.Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer's Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer's Disease Neuroimaging Initiative data set.Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined.Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance.It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD.
View details for DOI 10.1097/JGP.0b013e31820d92b2
View details for Web of Science ID 000292031900005
View details for PubMedID 21709609
HLA DQB1*0602 is found in most individuals with hypocretin-deficient narcolepsy, a disorder characterized by a severe disruption of sleep and wake. Population studies indicate that DQB1*0602 may also be associated with normal phenotypic variation of rapid eye movement (REM) sleep. Disruption of REM sleep has been linked to specific symptoms of insomnia. We here examine the relationship of sleep and DQB1*0602 in older individuals (n=46) with primary insomnia, using objective (polysomnography, wrist actigraphy) and subjective (logs, scales) measures. DQB1*0602 positivity was similarly distributed in the older individuals with insomnia (24%) as in the general population (25%). Most sleep variables were statistically indistinguishable between DQB1*0602 positive and negative subjects except that those with the allele reported that they were significantly less well rested than those without it. When sleep efficiencies were lower than 70%, DQB1*0602 positive subjects reported being less well rested at the same sleep efficiency than those without the allele. Examination of EEG during REM sleep also revealed that DQB1*0602 positive subjects had EEG shifted towards faster frequencies compared with negative subjects. Thus, DQB1*0602 positivity is associated with both a shift in EEG power spectrum to faster frequencies during REM sleep and a diminution of restedness given the same sleep quantity.
View details for DOI 10.1016/j.psychres.2011.01.007
View details for Web of Science ID 000290506500014
View details for PubMedID 21292329
Millions of individuals habitually expose themselves to room light in the hours before bedtime, yet the effects of this behavior on melatonin signaling are not well recognized.We tested the hypothesis that exposure to room light in the late evening suppresses the onset of melatonin synthesis and shortens the duration of melatonin production.In a retrospective analysis, we compared daily melatonin profiles in individuals living in room light (<200 lux) vs. dim light (<3 lux).Healthy volunteers (n = 116, 18-30 yr) were recruited from the general population to participate in one of two studies.Participants lived in a General Clinical Research Center for at least five consecutive days.Individuals were exposed to room light or dim light in the 8 h preceding bedtime.Melatonin duration, onset and offset, suppression, and phase angle of entrainment were determined.Compared with dim light, exposure to room light before bedtime suppressed melatonin, resulting in a later melatonin onset in 99.0% of individuals and shortening melatonin duration by about 90 min. Also, exposure to room light during the usual hours of sleep suppressed melatonin by greater than 50% in most (85%) trials.These findings indicate that room light exerts a profound suppressive effect on melatonin levels and shortens the body's internal representation of night duration. Hence, chronically exposing oneself to electrical lighting in the late evening disrupts melatonin signaling and could therefore potentially impact sleep, thermoregulation, blood pressure, and glucose homeostasis.
View details for DOI 10.1210/jc.2010-2098
View details for Web of Science ID 000288020600005
View details for PubMedID 21193540
We tested the hypothesis that single nucleotide polymorphisms (SNPs) in catechol-O-methyltransferase (COMT) are associated with apathy in individuals with Alzheimer's disease (AD). We analyzed a cohort of 105 Caucasian individuals with AD (age = 79.3 ± 7.03 years; MMSE = 20.2 ± 4.4) according to the presence of apathy, as defined either by the Neuropsychiatric Inventory or the Apathy Inventory. Polymorphisms in seventeen SNPs in COMT were examined. A replication cohort consisting of 176 Caucasian AD subjects in the ADNI database was also analyzed. None of the candidate gene SNPs were significantly associated with the presence of apathy in either cohort. We did not find any SNPs in COMT that were consistently associated with apathy in individuals with AD.
View details for DOI 10.3233/JAD-2011-110491
View details for Web of Science ID 000296570400014
View details for PubMedID 21785189
Apathy is the most frequently reported neuropsychiatric symptom across all stages of Alzheimer's disease (AD). Both apathy and sleep disorders are known to have independent negative effects on the quality of life in individuals with AD. The aim of this study was to assess the relationship between apathy and sleep/wake patterns in individuals with AD using ambulatory actigraphy. One hundred and three non-institutionalized individuals with AD wore a wrist actigraph continuously over seven consecutive 24-h periods. Apathy was assessed using the Neuropsychiatric Inventory. Daytime mean motor activity (dMMA) was calculated from daytime wrist actigraphy data. Actigraphic parameters of sleep included total sleep time (TST), wake after sleep onset (WASO), time in bed (TIB), WASO normalized by TIB, sleep latency, and nighttime mean motor activity (nMMA). Among the 103 individuals with AD (aged 76.9 ± 7.2 years; MMSE = 21.4 ± 4.3), those with apathy had significantly lower dMMA, higher WASO (both raw and normalized), and spent more time in bed during the night than those without apathy. Sleep latency, nMMA and TST did not differ significantly between the two subgroups. To our knowledge, this study is the first to identify a relationship between apathy and sleep disturbance in those with mild or moderate AD: apathy was associated with increased TIB during the night and more WASO. These results suggest that AD patients with apathy have less consolidated nocturnal sleep than those without apathy.
View details for DOI 10.3233/JAD-2011-101701
View details for Web of Science ID 000293377700009
View details for PubMedID 21335662
Sleep influences the cardiovascular, endocrine, and thermoregulatory systems. Each of these systems may be affected by the activity of hypocretin (orexin)-producing neurons, which are involved in the etiology of narcolepsy. We examined sleep in male rats, either hypocretin neuron-ablated orexin/ataxin-3 transgenic (narcoleptic) rats or their wild-type littermates. We simultaneously monitored electroencephalographic and electromyographic activity, core body temperature, tail temperature, blood pressure, electrocardiographic activity, and locomotion. We analyzed the daily patterns of these variables, parsing sleep and circadian components and changes between states of sleep. We also analyzed the baroreceptor reflex. Our results show that while core temperature and heart rate are affected by both sleep and time of day, blood pressure is mostly affected by sleep. As expected, we found that both blood pressure and heart rate were acutely affected by sleep state transitions in both genotypes. Interestingly, hypocretin neuron-ablated rats have significantly lower systolic and diastolic blood pressure during all sleep stages (non-rapid eye movement, rapid eye movement) and while awake (quiet, active). Thus, while hypocretins are critical for the normal temporal structure of sleep and wakefulness, they also appear to be important in regulating baseline blood pressure and possibly in modulating the effects of sleep on blood pressure.
View details for DOI 10.1152/japplphysiol.00516.2010
View details for Web of Science ID 000285344900016
View details for PubMedID 20705949
Studies of sex differences in the timing of human circadian rhythms have reported conflicting results. This may be because the studies conducted to date have not controlled for the masking effects of the rest activity cycle on the circadian rhythms being assessed. In the present analysis of data collected under controlled conditions, we examined sex differences in the timing of circadian rhythms while minimizing masking from behavioral and environmental factors using a constant routine (CR) protocol. All participants (28 women and 28 men paired by habitual wake time; age range, 18 30 years) maintained a regular self selected sleep wake schedule at home prior to the study. After 3 baseline days in the laboratory, participants began a CR. Women were found to have a significantly higher melatonin amplitude and lower temperature amplitude than men. While sleep timing was the same between the 2 groups, the timing of the circadian rhythms of core body temperature and pineal melatonin secretion was earlier relative to sleep time in women as compared to men. Sleep therefore occurred at a later biological time for women than men, despite being at the same clock time. Given that sleep propensity and structure vary with circadian phase and are impacted by circulating melatonin, these findings may have important implications for understanding sex differences in sleep timing and duration, diurnal preference, and the prevalence of sleep disorders such as insomnia.
View details for DOI 10.1177/0748730410374943
View details for Web of Science ID 000280610000006
View details for PubMedID 20679498
It is well established that the neuropeptide oxytocin (OT) is involved in regulating social behavior, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis physiology in mammals. Because individuals with major depression often exhibit functional irregularities in these measures, we test in this pilot study whether depressed subjects (n=11) exhibit dysregulated OT biology compared to healthy control subjects (n=19). Subjects were hospitalized overnight and blood samples were collected hourly between 1800 and 0900h. Plasma levels of OT, the closely related neuropeptide argine-vasopressin (AVP), and cortisol were quantified. Results indicated that depressed subjects exhibit increased OT levels compared to healthy control subjects, and this difference is most apparent during the nocturnal peak. No depression-related differences in AVP or cortisol levels were discerned. This depression-related elevation in plasma OT levels is consistent with reports of increased hypothalamic OT-expressing neurons and OT mRNA in depressed patients. This present finding is likewise consistent with the hypothesis that dysregulated OT biology may be a biomarker of the emotional distress and impaired social relationships which characterize major depression. Additional research is required to elucidate the role of OT in the pathophysiology of this psychiatric disorder.
View details for DOI 10.1016/j.psychres.2009.09.017
View details for Web of Science ID 000279988900025
View details for PubMedID 20494448
Hypocretin-1 is a hypothalamic neuropeptide that is important in the regulation of wake and the lack of which results in the sleep disorder narcolepsy. Using a monkey that has consolidated wake akin to humans, we examined pharmacological manipulation of sleep and wake and its effects on hypocretin physiology. Monkeys were given the sleep-inducing ?-hydroxybutyrate (GHB) and the wake-inducing modafinil both in the morning and in the evening. Cerebrospinal fluid hypocretin-1 concentrations changed significantly in response to the drugs only when accompanied by a behavioral change (GHB-induced sleep in the morning or modafinil-induced wake in the evening). We also found that there was a large (180-fold) interindividual variation in GHB pharmacokinetics that explains variability in sleep induction in response to the drug. Our data indicate that the neurochemical concomitants of sleep and wake are capable of changing the physiological output of hypocretin neurons. Sleep independent of circadian timing is capable of decreasing cerebrospinal fluid hypocretin-1 concentrations. Furthermore, hypocretin neurons do not seem to respond to an 'effort' to remain awake, but rather keep track of time spent awake as a wake-promoting counterbalance to extended wakefulness.
View details for DOI 10.1097/FBP.0b013e328331b9db
View details for Web of Science ID 000270483300010
View details for PubMedID 19752724
To determine whether bright light can improve sleep in older individuals with insomnia.Single-blind, placebo-controlled, 12-week, parallel-group randomized design comparing four treatment groups representing a factorial combination of two lighting conditions and two times of light administration.At-home light treatment; eight office therapy sessions.Thirty-six women and fifteen men (aged 63.6+/-7.1) meeting primary insomnia criteria recruited from the community.A 12-week program of sleep hygiene and exposure to bright ( approximately 4,000 lux) or dim light ( approximately 65 lux) scheduled daily in the morning or evening for 45 minutes.Within-group changes were observed for subjective (sleep logs, questionnaires) and objective (actigraphy, polysomnography) sleep measures after morning or evening bright light.Within-group changes for subjective sleep measures after morning or evening bright light were not significantly different from those observed after exposure to scheduled dim light. Objective sleep changes (actigraphy, polysomnography) after treatment were not significantly different between the bright and dim light groups. Scheduled light exposure was able to shift the circadian phase predictably but was unrelated to changes in objective or subjective sleep measures. A polymorphism in CLOCK predicted morningness but did not moderate the effects of light on sleep. The phase angle between the circadian system (melatonin midpoint) and sleep (darkness) predicted the magnitude of phase delays, but not phase advances, engendered by bright light.Except for one subjective measure, scheduled morning or evening bright light effects were not different from those of scheduled dim light. Thus, support was not found for bright light treatment of older individuals with primary insomnia.
View details for DOI 10.1111/j.1532-5415.2008.02164.x
View details for Web of Science ID 000263859600008
View details for PubMedID 19187411
Soldiers with a traumatic brain injury (TBI) present with an array of neuropsychiatric symptoms that can be grouped into nosological clusters: (1) cognitive dysfunctions: difficulties in memory, attention, language, visuospatial cognition, sensory-motor integration, affect recognition, and/or executive function typically associated with neocortical damage; (2) neurobehavioral disorders: mood, affect, anxiety, posttraumatic stress, and psychosis, as well as agitation, sleep problems, and libido loss, that may have been caused by damage to the cortex, limbic system, and/or brain stem monoaminergic projection systems; (3) somatosensory disruptions: impaired smell, vision, hearing, equilibrium, taste, and somatosensory perception frequently caused by trauma to the sensory organs or their projections through the brain stem to central processing systems; (4) somatic symptoms: headache and chronic pain; and (5) substance dependence. TBI-related cognitive impairment is common in veterans who have served in recent conflicts in the Middle East and is often related to blasts from improvised explosive devices. Although neurobehavioral disorders such as depression and posttraumatic stress disorder commonly occur after combat, the presentation of such disorders in those with head injury may pass undetected with use of current diagnostic criteria and neuropsychological instruments. With a multidimensional approach (such as the biopsychosocial model) applied to each symptom cluster, psychological, occupational, and social dysfunction can be delineated and managed.
View details for DOI 10.1682/JRRD.2008.08.0119
View details for Web of Science ID 000272638100010
View details for PubMedID 20104402
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in the United States. One of the most common comorbidities of TBI is the disruption of normal sleep. While often viewed as a nuisance symptom, sleep disruption can delay TBI recovery and negatively affect many of the psychological (e.g., anxiety, depression) and neuromuscular (e.g., pain) sequelae of TBI, decreasing quality of life. Treatment of sleep disruption in the context of TBI is complicated by issues of an altered neuronal milieu, polypharmacy, and the complex relationship between the various comorbidities often found in patients with TBI. Given the growing number of veterans returning from combat with TBI and the elevated risk of comorbid disrupted sleep, both caused by and independent of TBI, a comprehensive review of sleep disruption and its treatment is of great relevance to the Department of Veterans Affairs.
View details for DOI 10.1682/JRRD.2008.08.0099
View details for Web of Science ID 000272638100014
View details for PubMedID 20104406
Sleep apnea is prevalent among patients with traumatic brain injuries (TBIs), and initial studies suggest it is associated with cognitive impairments in these patients. Recent studies found that the apolipoprotein epsilon 4 (APOE epsilon 4) allele increases the risk for sleep disordered breathing, particularly sleep apnea. The APOE epsilon 4 allele is associated with cognitive decline and the development of dementia in the general population as well as in patients with TBI. These findings raise the question of whether patients with TBI who are APOE epsilon 4 allele carriers are more vulnerable to the negative effects of sleep apnea on their cognitive functioning. While few treatments are available for cognitive impairment, highly effective treatments are available for sleep apnea. Here we review these different lines of evidence, making a case that the interactive effects of sleep apnea and the APOE epsilon 4 allele represent an important mechanism by which patients with TBI may develop a range of cognitive and neurobehavioral impairments. Increased understanding of the relationships among sleep apnea, the APOE epsilon 4 allele, and cognition could improve our ability to ameliorate one significant source of cognitive impairment and risk for dementia associated with TBI.
View details for DOI 10.1682/JRRD.2008.10.0140
View details for Web of Science ID 000272638100015
View details for PubMedID 20104407
To determine the relationship between hypothalamic pituitary axis (HPA) dysregulation, vagal functioning, and sleep problems in women with metastatic breast cancer.Sleep was assessed by means of questionnaires and wrist actigraphy for 3 consecutive nights. The ambulatory, diurnal variation in salivary cortisol levels was measured at 5 time points over 2 days. Vagal regulation was assessed via respiratory sinus arrhythmia (RSA(TF)) during the Trier Social Stress Task.Ninety-nine women (54.6 +/- 9.62 years) with metastatic breast cancer.Longer nocturnal wake episodes (r = 0.21, p = 0.04, N=91) were associated with a flatter diurnal cortisol slope. Sleep disruption was also associated with diminished RSA(TF). Higher RSA baseline scores were significantly correlated with higher sleep efficiency (r = 0.39, p = 0.001, N=68) and correspondingly lower levels of interrupted sleep (waking after sleep onset, WASO; r = -0.38, p = 0.002, N=68), lower average length of nocturnal wake episodes (r = -0.43, p < 0.001, N=68), and a lower self-reported number of hours of sleep during a typical night (r = -0.27, p = 0.02, N=72). Higher RSA AUC was significantly related to higher sleep efficiency (r = 0.45, p < 0.001, N=64), and a correspondingly lower number of wake episodes (r = -0.27, p = 0.04, N=64), lower WASO (r = -0.40, p = 0.001, N=64), and with lower average length of nocturnal wake episodes (r = -0.41, p = 0.001, N=64). While demographics, disease severity, and psychological variables all explained some portion of the development of sleep disruption, 4 of the 6 sleep parameters examined (sleep efficiency, WASO, mean number of waking episodes, average length of waking episode) were best explained by RSA.These data provide preliminary evidence for an association between disrupted nocturnal sleep and reduced RSA the subsequent day, confirming an association between disrupted nocturnal sleep and flattened diurnal cortisol rhythm in women with metastatic breast cancer. They suggest that the stress-buffering effects of sleep may be associated with improved parasympathetic tone and normalized cortisol patterns during the day.
View details for PubMedID 18853702
Concentrations of CSF hypocretin-1 (formerly orexin A) have been measured in many patients with sleep or neurological conditions. Low CSF hypocretin-1 is most predictive of narcolepsy in patients positive for HLA allele DQB1*0602, most of whom have cataplexy. By contrast, the diagnostic significance of low CSF hypocretin-1 is unclear in the presence of acute CNS inflammation or trauma. The clinical usefulness of CSF testing in hypersomnia that is symptomatic of a neurological disorder remains to be evaluated. Determination of CSF hypocretin-1 concentration to diagnose narcolepsy might be most useful in ambulatory patients with cataplexy but with a normal multiple sleep latency test (MSLT) result, or if MSLT is not interpretable, conclusive, or feasible. Because 98% of patients with hypocretin-1 deficiency are positive for HLA DQB1*0602, we suggest that HLA typing is a useful screen before lumbar puncture. Although hypocretin-1 deficiency in narcolepsy might have therapeutic relevance, additional research is needed in this area.
View details for Web of Science ID 000257213600021
View details for PubMedID 18565458
Hippocampal volumes previously determined in monkeys by magnetic resonance imaging are used to test the hypothesis that small hippocampi predict increased stress levels of adrenocorticotropic hormone (ACTH).Plasma ACTH levels were measured after restraint stress in 19 male monkeys pretreated with saline or hydrocortisone. Monkeys were then randomized to an undisturbed control condition or intermittent social separations followed by new pair formations. After 17 months of exposure to the intermittent social manipulations, restraint stress tests were repeated to determine test/retest correlations.Individual differences in postrestraint stress ACTH levels over the 17-month test/retest interval were remarkably consistent for the saline (r(s) = .82, p = .0004) and hydrocortisone (r(s) = .78, p = .001) pretreatments. Social manipulations did not affect postrestraint stress ACTH levels, but monkeys with smaller hippocampal volumes responded to restraint after saline pretreatment with greater increases in ACTH levels with total brain volume variation controlled as a statistical covariate (beta = -.58, p = .031). Monkeys with smaller hippocampal volumes also responded with diminished sensitivity to glucocorticoid feedback determined by greater postrestraint ACTH levels after pretreatment with hydrocortisone (beta = -.68, p = .010).These findings support clinical reports that small hippocampi may be a risk factor for impaired regulation of the hypothalamic-pituitary-adrenal axis in humans with stress-related psychiatric disorders.
View details for DOI 10.1016/i.biopsych.2007.03.012
View details for Web of Science ID 000250905800015
View details for PubMedID 17573043
To determine the effects of sleep and sleep deprivation on plasma melatonin concentrations in humans and whether these effects are age-dependent.At least 2 weeks of regular at-home, sleep/wake schedule followed by 3 baseline days in the laboratory and at least one constant routine (sleep deprivation).General Clinical Research Center (GCRC), Brigham and Women's Hospital, Boston, MA.In Study 1, one group (<10 lux when awake) of 19 young men (18-30 y) plus a second group (<2 lux when awake) of 15 young men (20-28 y) and 10 young women (19-27 y); in Study 2, 90 young men (18-30 y), 18 older women (65-81 y), and 11 older men (64-75 y). All participants were in good health, as determined by medical and psychological screening.One to three constant routines with interspersed inversion of the sleep/wake cycle in those with multiple constant routines.Examination of plasma melatonin concentrations and core body temperature. Study 1. There was a small, but significant effect of sleep deprivation of up to 50 hours on melatonin concentrations (increase of 9.81 +/- 3.73%, P <0.05, compared to normally timed melatonin). There was also an effect of circadian phase angle with the prior sleep episode, such that if melatonin onset occurred <8 hours after wake time, the amplitude was significantly lower (22.4% +/- 4.79%, P <0.001). Study 2. In comparing melatonin concentrations during sleep to the same hours during constant wakefulness, in young men, melatonin amplitude was 6.7% +/- 2.1% higher(P <0.001) during the sleep episode. In older men, melatonin amplitude was 37.0% +/- 12.5% lower (P <0.05) during the sleep episode and in older women, melatonin amplitude was non-significantly 10.9% +/- 8.38% lower (P = 0.13) during the sleep episode.Both sleep and sleep deprivation likely influence melatonin amplitude, and the effect of sleep on melatonin appears to be age dependent.
View details for Web of Science ID 000250724600005
View details for PubMedID 18041478
The neuropeptides hypocretins (orexins), the loss of which results in the sleep disorder narcolepsy, are hypothesized to be involved in the consolidation of wakefulness and have been proposed to be part of the circadian-driven alertness signal. To elucidate the role of hypocretins in the consolidation of human wakefulness we examined the effect of wake extension on hypocretin-1 in squirrel monkeys, primates that consolidate wakefulness during the daytime as do humans. Wake was extended up to 7 h with hypocretin-1, cortisol, ghrelin, leptin, locomotion, and feeding, all being assayed. Hypocretin-1 (P < 0.01), cortisol (P < 0.001), and locomotion (P < 0.005) all increased with sleep deprivation, while ghrelin (P = 0.79) and leptin (P = 1.00) did not change with sleep deprivation. Using cross-correlation and multivariate modeling of these potential covariates along with homeostatic pressure (a measure of time awake/asleep), we found that time of day and homeostatic pressure together explained 44% of the variance in the hypocretin-1 data (P < 0.001), while cortisol did not significantly contribute to the overall hypocretin-1 variance. Locomotion during the daytime, but not during the nighttime, helped explain < 5% of the hypocretin-1 variance (P < 0.05). These data are consistent with earlier evidence indicating that in the squirrel monkey hypocretin-1 is mainly regulated by circadian inputs and homeostatic sleep pressure. Concomitants of wakefulness that affect hypocretin-1 in polyphasic species, such as locomotion, food intake, and food deprivation, likely have a more minor role in monophasic species, such as humans.
View details for DOI 10.1152/ajpregu.00460.2007
View details for Web of Science ID 000250088000033
View details for PubMedID 17686881
The rhythm of plasma melatonin concentration is currently the most accurate marker of the endogenous human circadian pacemaker. A number of methods exist to estimate circadian phase and amplitude from the observed melatonin rhythm. However, almost all these methods are limited because they depend on the shape and amplitude of the melatonin pulse, which vary among individuals and can be affected by environmental influences, especially light. Furthermore, these methods are not based on the underlying known physiology of melatonin secretion and clearance, and therefore cannot accurately quantify changes in secretion and clearance observed under different experimental conditions. A published physiologically-based mathematical model of plasma melatonin can estimate synthesis onset and offset of melatonin under dim light conditions. We amended this model to include the known effect of melatonin suppression by ocular light exposure and to include a new compartment to model salivary melatonin concentration, which is widely used in clinical settings to determine circadian phase. This updated model has been incorporated into an existing mathematical model of the human circadian pacemaker and can be used to simulate experimental protocols under a number of conditions.
View details for DOI 10.1111/j.1600-079X.2007.00477.x
View details for Web of Science ID 000249425400012
View details for PubMedID 17803528
Recent population studies have identified important interrelationships between sleep duration and body weight regulation. The hypothalamic hypocretin/orexin neuropeptide system is able to influence each of these. Disruption of the hypocretin system, such as occurs in narcolepsy, leads to a disruption of sleep and is often associated with increased body mass index. We examined the potential interrelationship between the hypocretin system, metabolism and sleep by measuring locomotion, feeding, drinking, body temperature, sleep/wake and energy metabolism in a mouse model of narcolepsy (ataxin-ablation of hypocretin-expressing neurons). We found that locomotion, feeding, drinking and energy expenditure were significantly reduced in the narcoleptic mice. These mice also exhibited severe sleep/wake fragmentation. Upon awakening, transgenic and control mice displayed a similar rate of increase in locomotion and food/water intake with time. A lack of long wake episodes partially or entirely explains observed differences in overall locomotion, feeding and drinking in these transgenic mice. Like other parameters, energy expenditure also rose and fell depending on the sleep/wake status. Unlike other parameters, however, energy expenditure in control mice increased upon awakening at a greater rate than in the narcoleptic mice. We conclude that the profound sleep/wake fragmentation is a leading cause of the reduced locomotion, feeding, drinking and energy expenditure in the narcoleptic mice under unperturbed conditions. We also identify an intrinsic role of the hypocretin system in energy expenditure that may not be dependent on sleep/wake regulation, locomotion, or food intake. This investigation illustrates the need for coordinated study of multiple phenotypes in mouse models with altered sleep/wake patterns.
View details for DOI 10.1113/jphysiol.2007.129510
View details for Web of Science ID 000246756000022
View details for PubMedID 17379635
Aging is associated with a change in the relationship between the timing of sleep and circadian rhythms, such that the rhythms occur later with respect to sleep than in younger adults. To investigate whether a difference in the phase-delaying response to evening light contributes to this, we conducted a 9-day inpatient study in 10 healthy older (> or =65 y.o.) subjects. We assessed circadian phase in a constant routine, exposed each subject to a 6.5h broad-spectrum light stimulus beginning in the early biological night, and reassessed circadian phase. The stimuli spanned a range from very dim (approximately 2 lx) to very bright (approximately 8000 lx) indoor light. We found a significant dose-response relationship between illuminance and the phase shift of the melatonin rhythm, with evidence that sensitivity, but not the maximal response to light, differed from that of younger adults. These findings suggest an age-related reduction in the phase-delaying response to moderate light levels. However, our findings alone do not explain the altered phase relationship between sleep and circadian rhythms associated with aging.
View details for DOI 10.1016/j.neurobiolaging.2006.03.005
View details for Web of Science ID 000245109700018
View details for PubMedID 16621166
The hypothalamic neuropeptide hypocretin (orexin) modulates sleep-wake, feeding and endocrine functions. Cerebrospinal fluid (CSF) hypocretin-1 (Hcrt-1) concentrations are low in patients with narcolepsy-cataplexy, a sleep disorder characterized by hypersomnolence and rapid eye movement (REM) sleep abnormalities.We determined CSF Hcrt-1 concentrations of patients with the fibromyalgia syndrome (FMS), a condition characterized by fatigue, insomnia and in some cases daytime hypersomnolence.Basal CSF levels of Hcrt-1 in FMS did not differ from those in healthy normal controls.These findings suggest that abnormally low Hcrt-1 is not a likely cause of fatigue in FMS.
View details for DOI 10.1016/j.sleep.2006.08.015
View details for Web of Science ID 000246343100010
View details for PubMedID 17369087
Narcolepsy is characterized by excessive daytime sleepiness, cataplexy and other manifestations of dissociated rapid eye movement sleep. Narcolepsy is typically treated with amphetamine-like stimulants (sleepiness) and antidepressants (cataplexy). Newer compounds, such as modafinil (non-amphetamine wake-promoting compound for excessive daytime sleepiness) and sodium oxybate (short-acting sedative for fragmented nighttime sleep, cataplexy, excessive daytime sleepiness), are increasingly used. Recent discoveries indicate that the major pathophysiology of human narcolepsy is the loss of lateral hypothalamic neurons that produce the neuropeptide hypocretin (orexin). Approximately 90% of people diagnosed as having narcolepsy with cataplexy are hypocretin ligand deficient. This has led to the development of new diagnostic tests (cerebrospinal fluid hypocretin-1 measurements). Hypocretin receptor agonists are likely to be ideal therapeutic options for hypocretin-deficient narcolepsy but such compounds are still not available in humans.
View details for DOI 10.1016/j.tips.2006.05.006
View details for Web of Science ID 000239368900005
View details for PubMedID 16766052
To examine the pattern of extracellular adenosine in the human brain during sleep deprivation, sleep, and normal wake.Following recovery from implantation of clinical depth electrodes, epilepsy patients remained awake for 40 continuous hours, followed by a recovery sleep episode.Neurology ward at UCLA Medical Center.Seven male epilepsy patients undergoing depth electrode localization of pharmacologically refractory seizures.All subjects were implanted with depth electrodes, a subset of which were customized to contain microdialysis probes. Microdialysis samples were collected during normal sleep, sleep deprivation, and recovery sleep from human amygdalae (n = 8), hippocampus (n = 1), and cortex (n = 1).In none of the probes did we observe an increase in extracellular adenosine during the sleep deprivation. There was a significant, though very small, diurnal oscillation (2.5%) in 5 of the 8 amygdalae. There was no effect of epileptogenicity on the pattern of extracellular adenosine.Our observations, along with those in animal studies, indicate that the role of extracellular adenosine in regulating sleep pressure is not a global brain phenomenon but is likely limited to specific basal forebrain areas. Thus, if energy homeostasis is a function of sleep, an increased rate of adenosine release into the extracellular milieu of the amygdala, cortex, or hippocampus is unlikely to be a marker of such a process.
View details for Web of Science ID 000237061300009
View details for PubMedID 16676778
Case-controlled preliminary observational study.Melatonin is usually secreted only at night and may influence sleep. We previously found that complete cervical spinal cord injury (SCI) interrupts the neural pathway required for melatonin secretion. Thus, we investigated whether the absence of night time melatonin in cervical SCI leads to sleep disturbances.General Clinical Research Center, Brigham and Women's Hospital, Boston, USA.In an ancillary analysis of data collected in a prior study, we assessed the sleep patterns of three subjects with cervical SCI plus absence of nocturnal melatonin (SCI levels: C4A, C6A, C6/7A) and two control patients with thoracic SCI plus normal melatonin rhythms (SCI levels: T4A, T5A). We also compared those results to the sleep patterns of 10 healthy control subjects.The subjects with cervical SCI had significantly lower sleep efficiency (median 83%) than the control subjects with thoracic SCI (93%). The sleep efficiency of subjects with thoracic SCI was not different from that of healthy control subjects (94%). There was no difference in the proportion of the different sleep stages, although there was a significantly increased REM-onset latency in subjects with cervical SCI (220 min) as compared to subjects with thoracic SCI (34 min). The diminished sleep in cervical SCI was not associated with sleep apnea or medication use.We found that cervical SCI is associated with decreased sleep quality. A larger study is required to confirm these findings. If confirmed, the absence of night time melatonin in cervical SCI may help explain their sleep disturbances, raising the possibility that melatonin replacement therapy could help normalize sleep in this group.
View details for DOI 10.1038/sj.sc.3101784
View details for Web of Science ID 000235068600002
View details for PubMedID 16130027
Kleine-Levin syndrome (KLS) is a rare disorder with symptoms that include periodic hypersomnia, cognitive and behavioural disturbances. Large series of patients are lacking. In order to report on various KLS symptoms, identify risk factors and analyse treatment response, we performed a systematic review of 195 articles, written in English and non-English languages, which are available on Medline dating from 1962 to 2004. Doubtful or duplicate cases, case series without individual details and reviews (n = 56 articles) were excluded. In addition, the details of 186 patients from 139 articles were compiled. Primary KLS cases (n = 168) were found mostly in men (68%) and occurred sporadically worldwide. The median age of onset was 15 years (range 4-82 years, 81% during the second decade) and the syndrome lasted 8 years, with seven episodes of 10 days, recurring every 3.5 months (median values) with the disease lasting longer in women and in patients with less frequent episodes during the first year. It was precipitated most frequently by infections (38.2%), head trauma (9%), or alcohol consumption (5.4%). Common symptoms were hypersomnia (100%), cognitive changes (96%, including a specific feeling of derealization), eating disturbances (80%), hypersexuality (43%), compulsions (29%), and depressed mood (48%). In 75 treated patients (213 trials), somnolence decreased using stimulants (mainly amphetamines) in 40% of cases, while neuroleptics and antidepressants were of poor benefit. Only lithium (but not carbamazepine or other antiepileptics) had a higher reported response rate (41%) for stopping relapses when compared to medical abstention (19%). Secondary KLS (n = 18) patients were older and had more frequent and longer episodes, but had clinical symptoms and treatment responses similar to primary cases. In conclusion, KLS is a unique disease which may be more severe in female and secondary cases.
View details for DOI 10.1093/brain/awh620
View details for Web of Science ID 000233667500004
View details for PubMedID 16230322
The light-dark cycle is the primary synchronizing factor that keeps the internal circadian pacemaker appropriately aligned with the environmental 24-h day. Although it is known that ocular light exposure can effectively shift the human circadian pacemaker and do so in an intensity-dependent manner, the curve that describes the relationship between light intensity and pacemaker response has not been fully characterized for light exposure in the late biological night. We exposed subjects to 3 consecutive days of 5 h of experimental light, centered 1.5 h after the timing of the fitted minimum of core body temperature, and show that such light can phase advance shift the human circadian pacemaker in an intensity-dependent manner, with a logistic model best describing the relationship between light intensity and phase shift. A similar sigmoidal relationship is also observed between light intensity and the suppression of plasma melatonin concentrations that occurs during the experimental light exposure. As with a simpler, 1-day light exposure during the early biological night, our data indicate that the human circadian pacemaker is highly sensitive even to typical room light intensities during the late biological night, with approximately 100 lux evoking half of the effects observed with light 10 times as bright.
View details for DOI 10.1152/ajpregu.00232.2005
View details for Web of Science ID 000231243700026
View details for PubMedID 15890792
Lesions along the sympathetic pathway to the eye produce oculosympathetic paresis (OSP, Horner's syndrome). The oculosympathetic pathway descends from the hypothalamus through the cervical spinal cord and ascends to the superior cervical ganglion (SCG), which innervates sympathetic targets in the ipsilateral face and eye. This pathway appears to closely co-localize with a similar retino-pineal neural pathway from the hypothalamus through the cervical spinal cord and SCG to the pineal gland. As such, lesions along this shared pathway, such as occur in neurologically complete injury to the cervical spinal cord (tetraplegia), would be predicted to result in simultaneous OSP and loss of pineal melatonin production. Loss of melatonin production may contribute to the pervasive sleep disruption observed in patients with tetraplegia.We assessed the presence of OSP by photographic documentation of ptosis and pupillary dilation response to cocaine eye drops in 5 individuals with neurologically complete damage to their upper thoracic or lower cervical spinal cord. We correlated these results with an analysis of the pattern of melatonin production in these same individuals.Bilateral OSP was present in individuals with cervical spinal cord injury; each also lacked significant production of melatonin. No evidence of OSP was observed in the 2 individuals with thoracic spinal cord injury below the level of the oculosympathetic pathway. Both had normal circadian rhythms of melatonin production, with timing and amplitude of the rhythm within normal parameters.The presence of bilateral oculosympathetic paresis can be predictive of the complete loss of the nocturnal production of melatonin.
View details for Web of Science ID 000234835600012
View details for PubMedID 15832904
Hypocretins (orexins) are involved in the sleep disorder narcolepsy. While hypocretin-1 has a daily oscillation, little is known regarding the relative contribution of circadian and homeostatic components on hypocretin release. The effect of lesions of the suprachiasmatic nucleus (SCN) on hypocretin-1 in the cerebrospinal fluid (CSF) was examined.SCN-ablated (SCNx) and sham-operated control rats were implanted with activity-temperature transmitters. Animals were housed individually under 1 of 3 lighting conditions: 12-hour:12-hour light:dark cycle (LD), constant light (LL), and constant darkness (DD). Lesions were verified histologically and shown not to affect hypocretin-containing cells. Hypocretin-1 concentrations in the CSF were determined every 4 hours using radioimmunoassays.Control animals displayed robust circadian (LL, DD) and diurnal (LD) fluctuations in CSF hypocretin-1, locomotor activity, and temperature. Peak CSF hypocretin-1 was at the end of the active period. Activity, temperature, and CSF hypocretin-1 were arrhythmic in SCNx animals in LL and DD. In LD, a weak but significant fluctuation in activity and temperature but not CSF hypocretin-1 was observed in SCNx animals. We also explored correlations between CSF hypocretin-1, CSF corticosterone, and locomotor activity occurring prior to CSF sampling in arrhythmic SCNx rats under constant conditions. Significant correlations between hypocretin-1 and activity were observed both across and within animals, suggesting that interindividual and time-of-the-day differences in activity have significant effects on hypocretin release in arrhythmic animals. No correlation was found between CSF hypocretin-1 and corticosterone.Hypocretin-1 release is under SCN control. Locomotor activity influences the activity of the hypocretin neurons.
View details for Web of Science ID 000223169300007
View details for PubMedID 15282996
The hypocretin system is involved in the integration of hypothalamic functions with sleep and wake. Hypocretin-1 release peaks at the end of the active period in both diurnal and nocturnal species. A role for hypocretin-1 in the generation of locomotor activity has been suggested by electrophysiological and neurochemical studies in rodents, dogs and cats. These species, however, do not consolidate wake into a single, daily bout and manipulations of locomotion elicit changes in wakefulness, making it difficult to parse the relative contribution of these two factors. We have examined the relationship between locomotion and hypocretin-1 in a wake-consolidating animal, the squirrel monkey (Saimiri sciureus). Strikingly, we found that restricting locomotion to 17% of usual activity had no significant effect on the normal diurnal rise in cerebrospinal fluid (CSF) hypocretin-1, despite an associated increase in CSF cortisol. Increasing locomotion to greater than baseline activity did not significantly increase CSF hypocretin-1 concentrations, but did appear to have a positive modulatory effect on CSF hypocretin-1. In this wake-consolidating animal, locomotion is not necessary for CSF hypocretin-1 to increase throughout the daytime, but high levels of locomotion are likely to provide a small positive feedback onto the hypocretin system.
View details for DOI 10.1113/jphysiol.2004.061606
View details for Web of Science ID 000222403700029
View details for PubMedID 15107479
Hypocretins, excitatory neuropeptides at monoaminergic synapses, appear to regulate human sleep-wake cycles. Undetectable cerebrospinal fluid hypocretin-1 levels are seen in narcolepsy, which is frequently associated with secondary depression. Shortened rapid eye movement latency is observed in both narcolepsy and depression. Cerebrospinal fluid hypocretin-1 levels have not been reported in mood disorders.We examined hypocretin-1 levels in 14 control and 15 depressed subjects. Cerebrospinal fluid was drawn continuously in supine subjects for 24 hours with an indwelling intrathecal catheter under entrained light-dark conditions. Depressed subjects were studied before and after 5 weeks of sertraline (n=10, three nonresponders) or bupropion (n=5, two nonresponders).Hypocretin-1 levels varied slightly (amplitude 10%) but significantly across the diurnal cycle in control subjects, with amplitude significantly reduced in depression (3%). Levels were lowest at midday, surprising for a hypothetically wake-promoting peptide. Mean hypocretin levels trended higher in depressive than in control subjects. Hypocretin-1 levels decreased modestly but significantly after sertraline (-14%) but not bupropion.Our results are consistent with previous physiologic findings in depression indicating dampened diurnal variations in hypocretin-1. The finding that sertraline but not bupropion slightly decreased cerebrospinal fluid hypocretin-1 indicates a serotoninergic influence on hypocretin tone.
View details for DOI 10.1016/S0006-3223(03)01740-7
View details for Web of Science ID 000184213800002
View details for PubMedID 12873798
In humans, consolidation of wakefulness into a single episode can be modeled as the interaction of two processes, a homeostatic "hour-glass" wake signal that declines throughout the daytime and a circadian wake-promoting signal that peaks in the evening. Hypocretins, novel hypothalamic neuropeptides that are dysfunctional in the sleep disorder narcolepsy, may be involved in the expression of the circadian wake-promoting signal. Hypocretins (orexins) are wake-promoting peptides, but their role in normal human sleep physiology has yet to be determined. We examined the daily temporal pattern of hypocretin-1 in the cisternal CSF of the squirrel monkey, a New World primate with a pattern of wake similar to that of humans. Hypocretin-1 levels peaked in the latter third of the day, consistent with the premise that hypocretin-1 is involved in wake regulation. When we lengthened the wake period by 4 hr, hypocretin-1 concentrations remained elevated, indicating a circadian-independent component to hypocretin-1 regulation. Changes in the stress hormone cortisol were not correlated with hypocretin-1 changes. Although hypocretin-1 is at least partially activated by a reactive homeostatic mechanism, it is likely also regulated by the circadian pacemaker. In the squirrel monkey, hypocretin-1 works in opposition to the accumulating sleep drive during the day to maintain a constant level of wake.
View details for Web of Science ID 000182475200052
View details for PubMedID 12716965
To correlate glucose (and lactate) results obtained from microdialysate to recent studies suggesting that glucose transporter activity may be significantly altered in seizures.We used a fluorometric technique to quantify glucose and lactate levels in microdialysates collected from two to four depth electrodes implanted per patient in the temporal and frontal lobes of a series of four patients. Hour-by-hour and day-to-day changes in brain glucose and lactate levels at the same site were recorded. Additionally we compared regional variations in lactate/glucose ratios around the predicted epileptogenic region.Lactate/glucose ratios in the range of 1-2:1 were the most commonly seen. When the lactate/glucose ratio was <1:1, we typically observed a relative increase in local glucose concentration (rather than decreased lactate), suggesting increased transport, perhaps without increased glycolysis. In some sites, lactate/glucose ratios of 3:1-15:1 were seen, suggesting that a circumscribed zone of inhibition of tricarboxylic acid cycle activity may have been locally induced. In these dialysates, collected from probes closer to the epileptogenic region, the large increase in lactate/glucose ratios was a result of both increased lactate and reduced glucose levels.We conclude that regional variations in brain extracellular glucose concentrations may be of greater magnitude than previously believed and become even more accentuated in partial seizure patients. Data from concomitant assays of microdialysate lactate and glucose may aid in understanding cerebral metabolism.
View details for Web of Science ID 000179307900011
View details for PubMedID 12423386
Serotonin is thought to be intimately involved in the regulation of sleep and waking in humans, though the evidence for such is indirect. Using in vivo microdialysis, the authors show that serotonin in human ventricular CSF covaries with the state of consciousness. They hypothesize that CSF serotonin may be acting in an endocrine-like manner through activation of known leptomeningeal serotonin receptors and possibly participating in modulation of choroidal production of CSF.
View details for Web of Science ID 000178726700033
View details for PubMedID 12391366
We investigated the relationship between sleep timing and the timing of the circadian rhythm of plasma melatonin secretion in a group of healthy young and older subjects without sleep complaints. The timing of sleep and the phase of the circadian melatonin rhythm were earlier in the older subjects. The relationship between the plasma melatonin rhythm and the timing of sleep was such that the older subjects were sleeping and waking earlier relative to their nightly melatonin secretory episode. Consequently, the older subjects were waking at a time when they had higher relative melatonin levels, in contrast with younger subjects, whose melatonin levels were relatively lower by wake time. Our findings indicate that aging is associated not only with an advance of sleep timing and the timing of circadian rhythms but also with a change in the internal phase relationship between the sleep-wake cycle and the output of the circadian pacemaker. In healthy older subjects, the relative timing of the melatonin rhythm with respect to sleep may not play a causal role in sleep disruption.
View details for Web of Science ID 000173460600007
View details for PubMedID 11788360
The hypocretins (orexins) are two novel neuropeptides (Hcrt-1 and Hcrt-2), derived from the same precursor gene, that are synthesized by neurons located exclusively in the lateral, posterior, and perifornical hypothalamus. Hypocretin-containing neurons have widespread projections throughout the CNS with particularly dense excitatory projections to monoaminergic centers such as the noradrenergic locus coeruleus, histaminergic tuberomammillary nucleus, serotoninergic raphe nucleus, and dopaminergic ventral tegmental area. The hypocretins were originally believed to be primarily important in the regulation of appetite; however, a major function emerging from research on these neuropeptides is the regulation of sleep and wakefulness. Deficiency in hypocretin neurotransmission results in the sleep disorder narcolepsy in mice, dogs, and humans. The hypocretins are also uniquely positioned to link sleep, appetite, and neuroendocrine control. The aim of this review is to describe and discuss the current knowledge regarding the hypocretin neurotransmitter system in narcolepsy and normal sleep.
View details for DOI 10.1146/annurev.neuro.25.112701.142826
View details for Web of Science ID 000177354800009
View details for PubMedID 12052911
The daily rhythm of melatonin influences multiple physiological measures, including sleep tendency, circadian rhythms, and reproductive function in seasonally breeding mammals. The biological signal for photoperiodic changes in seasonally breeding mammals is a change in the duration of melatonin secretion, which in a natural environment reflects the different durations of daylight across the year, with longer nights leading to a longer duration of melatonin secretion. These seasonal changes in the duration of melatonin secretion do not simply reflect the known acute suppression of melatonin secretion by ocular light exposure, but also represent long-term changes in the endogenous nocturnal melatonin episode that persist in constant conditions. As the eyes of totally blind individuals do not transmit ocular light information, we hypothesized that the duration of the melatonin secretory episode in blind subjects would be longer than those in sighted individuals, who are exposed to light for all their waking hours in an urban environment. We assessed the melatonin secretory profile during constant posture, dim light conditions in 17 blind and 157 sighted adults, all of whom were healthy and using no prescription or nonprescription medications. The duration of melatonin secretion was not significantly different between blind and sighted individuals. Healthy blind individuals after years without ocular light exposure do not have a longer duration of melatonin secretion than healthy sighted individuals.
View details for Web of Science ID 000169838300042
View details for PubMedID 11443183
View details for Web of Science ID 000175403700077
Light can elicit both circadian and acute physiological responses in humans. In a dose response protocol men and women were exposed to illuminances ranging from 3 to 9100 lux for 6.5 h during the early biological night after they had been exposed to <3 lux for several hours. Light exerted an acute alerting response as assessed by a reduction in the incidence of slow-eye movements, a reduction of EEG activity in the theta-alpha frequencies (power density in the 5-9 Hz range) as well as a reduction in self-reported sleepiness. This alerting response was positively correlated with the degree of melatonin suppression by light. In accordance with the dose response function for circadian resetting and melatonin suppression, the responses of all three indices of alertness to variations in illuminance were consistent with a logistic dose response curve. Half of the maximum alerting response to bright light of 9100 lux was obtained with room light of approximately 100 lux. This sensitivity to light indicates that variations in illuminance within the range of typical, ambient, room light (90-180 lux) can have a significant impact on subjective alertness and its electrophysiologic concomitants in humans during the early biological night.
View details for Web of Science ID 000089374500009
View details for PubMedID 10996410
Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non-linear relationship to illuminance. The dose-response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. Twenty-three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. We demonstrate that humans are highly responsive to the phase-delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose-response curve, as do many circadian responses to light in mammals. Contrary to expectations, we found that half of the maximal phase-delaying response achieved in response to a single episode of evening bright light ( approximately 9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of approximately 100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.
View details for Web of Science ID 000089202500022
View details for PubMedID 10922269
The human circadian timing system regulates the temporal organization of several endocrine functions, including the production of melatonin (via a neural pathway that includes the spinal cord), TSH, and cortisol. In traumatic spinal cord injury, afferent and efferent circuits that influence the basal production of these hormones may be disrupted. We studied five subjects with chronic spinal cord injury (three tetraplegic and two paraplegic, all neurologically complete injuries) under stringent conditions in which the underlying circadian rhythmicity of these hormones could be examined. Melatonin production was absent in the three tetraplegic subjects with injury to their lower cervical spinal cord and was of normal amplitude and timing in the two paraplegic subjects with injury to their upper thoracic spinal cord. The amplitude and the timing of TSH and cortisol rhythms were robust in the paraplegics and in the tetraplegics. Our results indicate that neurologically complete cervical spinal injury results in the complete loss of pineal melatonin production and that neither the loss of melatonin nor the loss of spinal afferent information disrupts the rhythmicity of cortisol or TSH secretion.
View details for Web of Science ID 000088460500023
View details for PubMedID 10852451
Numerous reports that secretion of the putative sleep-promoting hormone melatonin declines with age have led to suggestions that melatonin replacement therapy be used to treat sleep problems in older patients. We sought to reassess whether the endogenous circadian rhythm of plasma melatonin concentration changes with age in healthy drug-free adults.We analyzed the amplitude of plasma melatonin profiles during a constant routine in 34 healthy drug-free older subjects (20 women and 14 men, aged 65 to 81 years) and compared them with 98 healthy drug-free young men (aged 18 to 30 years).We could detect no significant difference between a healthy and drug-free group of older men and women as compared to one of young men in the endogenous circadian amplitude of the plasma melatonin rhythm, as described by mean 24-hour average melatonin concentration (70 pmol/liter vs 73 pmol/liter, P = 0.97), or the duration (9.3 hours vs 9.1 hours, P = 0.43), mean (162 pmol/liter vs 161 pmol/liter, P = 0.63), or integrated area (85,800 pmol x min/liter vs 86,700 pmol x min/liter, P = 0.66) of the nocturnal peak of plasma melatonin.These results do not support the hypothesis that reduction of plasma melatonin concentration is a general characteristic of healthy aging. Should melatonin replacement therapy or melatonin supplementation prove to be clinically useful, we recommend that an assessment of endogenous melatonin be carried out before such treatment is used in older patients.
View details for Web of Science ID 000083583900004
View details for PubMedID 10569297
The endogenous circadian rhythm of melatonin in humans provides information regarding the resetting response of the human circadian timing system to changes in the light-dark (LD) cycle. Alterations in the LD cycle have both acute and chronic effects on the observed melatonin rhythm. Investigations to date have firmly established that the melatonin rhythm can be reentrained following an inversion of the LD cycle. Exposure to bright light and darkness given over a series of days can rapidly induce large-magnitude phase shifts of the melatonin rhythm. Even single pulses of bright light can shift the timing of the melatonin rhythm. Recent data have demonstrated that lower light intensities than originally believed are capable of resetting the melatonin rhythm and that stimulation of photopically sensitive photoreceptors (i.e., cones) is sufficient to reset the endogenous circadian melatonin rhythm. In addition to phase resetting, exposure to light of critical timing, strength, and duration can attenuate the amplitude of the endogenous circadian rhythm of melatonin. Measurement of melatonin throughout resetting trials provides a dynamic view of the resetting response of the human circadian pacemaker to light. Future studies of the melatonin rhythm in humans may further characterize the resetting response of the human circadian timing system to light.
View details for Web of Science ID A1997YJ44900010
View details for PubMedID 9406030
Despite the preeminence of light as the synchronizer of the circadian timing system, the phototransductive machinery in mammals which transmits photic information from the retina to the hypothalamic circadian pacemaker remains largely undefined. To determine the class of photopigments which this phototransductive system uses, we exposed a group (n = 7) of human subjects to red light below the sensitivity threshold of a scotopic (i.e. rhodopsin/rod-based) system, yet of sufficient strength to activate a photopic (i.e. cone-based) system. Exposure to this light stimulus was sufficient to reset significantly the human circadian pacemaker, indicating that the cone pigments which mediate color vision can also mediate circadian vision.
View details for Web of Science ID A1997XV84100004
View details for PubMedID 9310298
View details for Web of Science ID 000318009800188
View details for Web of Science ID 000265542001152
View details for Web of Science ID 000246224900882
View details for Web of Science ID 000174927200019