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1.
Clin Pharmacol Ther ; 86(4): 378-82, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19606092

ABSTRACT

Oral melatonin (MEL) can improve daytime sleep, but the hormone's short elimination half-life limits its use as a hypnotic in shift workers and individuals with jet lag or other sleep problems. Here we show, in healthy subjects, that transdermal delivery of MEL during the daytime can elevate plasma MEL and reduce waking after sleep onset, by promoting sleep in the latter part of an 8-h sleep opportunity. Transdermal MEL may have advantages over fast-release oral MEL in improving sleep maintenance during adverse circadian phases.


Subject(s)
Central Nervous System Depressants/therapeutic use , Melatonin/therapeutic use , Sleep Disorders, Circadian Rhythm/drug therapy , Administration, Cutaneous , Adult , Body Temperature , Central Nervous System Depressants/administration & dosage , Circadian Rhythm/physiology , Cross-Over Studies , Delayed-Action Preparations , Double-Blind Method , Electroencephalography/drug effects , Female , Half-Life , Humans , Male , Melatonin/administration & dosage , Sex Factors , Sleep/drug effects
2.
Am J Vet Res ; 65(9): 1279-83, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15478778

ABSTRACT

OBJECTIVE: To evaluate the use of immunofluorescence asssays for perinuclear antineutrophilic cytoplasmic antibodies (pANCAs) and antibodies to Saccharomyces cerevisiae (ASCAs) in dogs with inflammatory bowel disease (IBD) and assess the clinical value of these serologic markers of the disease. ANIMALS: 39 dogs with IBD, 18 dogs with acute diarrhea, 19 dogs with chronic non-IBD-associated diarrhea, 26 healthy dogs of various breeds and age, and 22 healthy young working dogs. PROCEDURE: Sera obtained from the dogs in each group were added to canine granulocyte- and Saccharomyces cerevisiae-mounted slides for detection of pANCAs and ASCAs via immunofluorescence techniques. Sensitivity and specificity (with 95% confidence intervals [CIs]) were calculated for the group of dogs with IBD versus each of the 2 groups of healthy dogs, the group of dogs with acute diarrhea, and the group of dogs with chronic non-IBD-associated diarrhea. RESULTS: Among the 39 dogs with IBD, 20 yielded positive results via the pANCA assay (sensitivity, 0.51 [95% CI, 0.35 to 0.67]) and 17 yielded positive results via the ASCA assay (sensitivity, 0.44 [95% CI, 0.22 to 0.69]). The specificity of the pANCA assay in the 4 groups of non-IBD-affected dogs ranged from 0.83 (95% CI, 0.85 to 0.96) to 0.95 (95% CI, 0.72 to 1.00). CONCLUSIONS AND CLINICAL RELEVANCE: Immunofluorescence assays for pANCA and ASCA appear to be useful for the detection of IBD in dogs. The pANCA immunofluorescence assay had high specificity for canine IBD, and pANCAs appear to be accurate markers of intestinal inflammation.


Subject(s)
Antibodies, Antineutrophil Cytoplasmic/immunology , Antibodies, Fungal/immunology , Dog Diseases/immunology , Dog Diseases/microbiology , Fluorescent Antibody Technique, Indirect/methods , Inflammatory Bowel Diseases/veterinary , Saccharomyces cerevisiae/immunology , Animals , Biomarkers/blood , Dog Diseases/blood , Dogs , Evaluation Studies as Topic , Inflammatory Bowel Diseases/blood , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/microbiology
3.
Arch Gen Psychiatry ; 58(12): 1108-14, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11735838

ABSTRACT

BACKGROUND: In animals, the circadian pacemaker regulates seasonal changes in behavior by transmitting a signal of day length to other sites in the organism. The signal is expressed reciprocally in the duration of nocturnal melatonin secretion, which is longer in winter than in summer. We investigated whether such a signal could mediate the effects of change of season on patients with seasonal affective disorder. METHODS: The duration of melatonin secretion in constant dim light was measured in winter and in summer in 55 patients and 55 matched healthy volunteers. Levels of melatonin were measured in plasma samples that were obtained every 30 minutes for 24 hours in each season. RESULTS: Patients and volunteers responded differently to change of season. In patients, the duration of the nocturnal period of active melatonin secretion was longer in winter than in summer (9.0 +/- 1.3 vs 8.4 +/- 1.3 hours; P=.001) but in healthy volunteers there was no change (9.0 +/- 1.6 vs 8.9 +/- 1.2 hours; P=.5). CONCLUSIONS: The results show that patients with seasonal affective disorder generate a biological signal of change of season that is absent in healthy volunteers and that is similar to the signal that mammals use to regulate seasonal changes in their behavior. While not proving causality, this finding is consistent with the hypothesis that neural circuits that mediate the effects of seasonal changes in day length on mammalian behavior mediate effects of season and light treatment on seasonal affective disorder.


Subject(s)
Circadian Rhythm/physiology , Melatonin/blood , Seasonal Affective Disorder/physiopathology , Seasons , Adult , Female , Humans , Hypothalamus/physiopathology , Male , Middle Aged , Nerve Net/physiopathology , Reference Values , Seasonal Affective Disorder/diagnosis , Seasonal Affective Disorder/psychology
4.
J Physiol ; 535(Pt 3): 937-51, 2001 Sep 15.
Article in English | MEDLINE | ID: mdl-11559786

ABSTRACT

1. Because individuals differ in the phase angle at which their circadian rhythms are entrained to external time cues, averaging group data relative to clock time sometimes obscures abrupt changes that are characteristic of waveforms of the rhythms in individuals. Such changes may have important implications for the temporal organization of human circadian physiology. 2. To control for variance in phase angle of entrainment, we used dual internal reference points--onset and offset of the nocturnal period of melatonin secretion--to calculate average profiles of circadian rhythm data from five previously published studies. 3. Onset and/or offset of melatonin secretion were found to coincide with switch-like transitions between distinct diurnal and nocturnal periods of circadian rhythms in core body temperature, sleepiness, power in the theta band of the wake EEG, sleep propensity and rapid eye movement (REM) sleep propensity. 4. Transitions between diurnal and nocturnal periods of sleep-wake and cortisol circadian rhythms were found to lag the other transitions by 1-3 h. 5. When the duration of the daily light period was manipulated experimentally, melatonin-onset-related transitions in circadian rhythms appeared to be entrained to the light-to-dark transition, while melatonin-offset-related transitions appeared to be entrained to the dark-to-light transition. 6. These results suggest a model of the human circadian timing system in which two states, one diurnal and one nocturnal, alternate with one another, and in which transitions between the states are switch-like and are separately entrained to dawn and dusk. 7. This description of the human circadian system is similar to the Pittendrigh-Daan model of the rodent circadian system, and it suggests that core features of the system in other mammals are conserved in humans.


Subject(s)
Circadian Rhythm/physiology , Body Temperature/physiology , Electroencephalography , Environment , Humans , Hydrocortisone/blood , Melatonin/blood , Photoperiod , Polysomnography , Radioimmunoassay , Sleep Stages/physiology , Sleep, REM/physiology
5.
Neuroscience ; 102(3): 493-502, 2001.
Article in English | MEDLINE | ID: mdl-11226688

ABSTRACT

We used the waking electroencephalogram to study the homeostatic sleep regulatory process in human short sleepers and long sleepers. After sleeping according to their habitual schedule, nine short sleepers (sleep duration < 6 h) and eight long sleepers (> 9 h) were recorded half-hourly during approximately 40 h of wakefulness in a constant routine protocol. Within the frequency range of 0.25-20.0 Hz, spectral power density in the 5.25-9.0 and 17.25-18.0 Hz ranges was higher in short sleepers than in long sleepers. In both groups, increasing time awake was associated with an increase of theta/low-frequency alpha activity (5.25-9.0 Hz), whose kinetics followed a saturating exponential function. The time constant did not differ between groups and was similar to the previously obtained time constant of the wake-dependent increase of slow-wave activity (0.75-4.5 Hz) in the sleep electroencephalogram. In addition, the time constant of the decrease of slow-wave activity during extended recovery sleep following the constant routine did not differ between groups. However, short sleepers showed an abiding enhancement of theta/low-frequency alpha activity during wakefulness after recovery sleep that was independent of the homeostatic process. It is concluded that, while the kinetics of the homeostatic process do not differ between the two groups, short sleepers live under and tolerate higher homeostatic sleep pressure than long sleepers. The homeostat-independent enhancement of theta/low-frequency alpha activity in the waking electroencephalogram in the short sleepers may be genetically determined or be the result of long-term adaptation to chronically short sleep.


Subject(s)
Circadian Rhythm/physiology , Electroencephalography , Sleep/physiology , Wakefulness/physiology , Adult , Body Temperature , Female , Homeostasis , Humans , Male , Sleep Stages/physiology
6.
Am J Physiol ; 277(6): R1771-9, 1999 12.
Article in English | MEDLINE | ID: mdl-10600925

ABSTRACT

The influence of the circadian pacemaker and of the duration of time awake on the electroencephalogram (EEG) was investigated in 19 humans during approximately 40 h of sustained wakefulness. Two circadian rhythms in spectral power density were educed. The first rhythm was centered in the theta band (4.25-8.0 Hz) and exhibited a minimum approximately 1 h after the onset of melatonin secretion. The second rhythm was centered in the high-frequency alpha band (10.25-13.0 Hz) and exhibited a minimum close to the body temperature minimum. The latter rhythm showed a close temporal association with the rhythms in subjective alertness, plasma melatonin, and body temperature. In addition, increasing time awake was associated with an increase of power density in the 0.25- to 9.0-Hz and 13.25- to 20. 0-Hz ranges. It is concluded that the waking EEG undergoes changes that can be attributed to circadian and homeostatic (i.e., sleep-wake dependent) processes. The distinct circadian variations of EEG activity in the theta band and in the high-frequency alpha band may represent electrophysiological correlates of different aspects of the circadian rhythm in arousal.


Subject(s)
Biological Clocks , Circadian Rhythm/physiology , Electroencephalography , Melatonin/metabolism , Wakefulness/physiology , Adult , Body Temperature , Body Temperature Regulation , Female , Homeostasis , Humans , Male , Melatonin/blood
7.
Psychiatry Clin Neurosci ; 52(2): 129-30, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9628109

ABSTRACT

In the framework of a selective sleep deprivation study, eight young men were repeatedly awakened during 3 nights from nonREM sleep (nonREMS). The mean number of awakenings per night was 27.4, 29.5 and 32.8. In order to avoid excessive suppression of slow wave sleep, no awakening occurred in the first nonREMS episode. Compared to baseline, cycle 2 was significantly prolonged in all 3 nights, and cycle 3 in night 3 only. However, after subtracting the waking intervals, the differences from baseline was eliminated. The results show that the mechanisms underlying sleep cycle control keep track of sleep time and disregard epochs of waking.


Subject(s)
Sleep Deprivation/physiology , Sleep Stages/physiology , Sleep, REM/physiology , Wakefulness/physiology , Adult , Cerebral Cortex/physiology , Humans , Male , Polysomnography
8.
Am J Physiol ; 274(4): R1186-94, 1998 04.
Article in English | MEDLINE | ID: mdl-9575987

ABSTRACT

To investigate rapid eye movement (REM) sleep regulation, eight healthy young men were deprived of REM sleep for three consecutive nights. In a three-night control sleep deprivation (CD) session 2 wk later, the subjects were repeatedly awakened from non-REM sleep in an attempt to match the awakenings during the REM sleep deprivation (RD) nights. During the RD nights the number of sleep interruptions required to prevent REM sleep increased within and across consecutive nights. REM sleep was reduced to 9.2% of baseline (CD nights: 80.7%) and rose to 140.1% in the first recovery night. RD gave rise to changes in the EEG power spectra of REM sleep. Power in the 8.25- to 11-Hz range was reduced in the first recovery night, an effect that gradually subsided but was still present in the third recovery night. The rising REM sleep propensity, as reflected by the increase of interventions within and across RD nights, and the moderate REM sleep rebound during recovery can be accounted for by a compensatory response that serves REM sleep homeostasis. The changes in the electroencephalogram power spectra, which were observed during enhanced REM sleep propensity, may be a sign of an altered quality of REM sleep.


Subject(s)
Electroencephalography , Sleep Deprivation/physiology , Sleep, REM/physiology , Sleep/physiology , Adult , Affect/physiology , Alpha Rhythm , Arousal/physiology , Body Temperature/physiology , Humans , Male , Rectum/physiology
9.
Brain Res ; 748(1-2): 131-6, 1997 Feb 14.
Article in English | MEDLINE | ID: mdl-9067453

ABSTRACT

The dynamics of EEG spindle frequency activity (SFA; spectral power density in the 12.25-15.0 Hz range) and its relationship to slow-wave activity (SWA; 0.75-4.5 Hz) were investigated in long sleep episodes (> 12 h). Young healthy men went to bed at either 19:00 h (early sleep; prior waking 36 h, n = 9) or 24:00 h (late sleep; prior waking 17 h, n = 8). In both nights, SWA in non-rapid-eye-movement sleep (NREMS) decreased over the first three to four 1.5-h intervals and remained at a low level in the subsequent five to six 1.5-h intervals. In contrast, the changes of SFA were more variable and differed between the lower (12.25-13.0 Hz), middle (13.25-14.0 Hz) and higher frequency bin (14.25-15.0 Hz). A pronounced influence of time of day was present in the lower and higher SFA bin, when the dynamics were analyzed with respect to clock time. In both the early and late sleep condition, power density in the lower bin was highest between 2:00 and 5:00 h in the morning and decreased thereafter. In the higher bin, power density was low in the early morning hours and increased as sleep was extended into the daytime hours. The results provide further evidence for a frequency-specific circadian modulation of SFA which becomes more evident at a time when SWA is low.


Subject(s)
Circadian Rhythm , Electroencephalography , Sleep Stages/physiology , Sleep/physiology , Adult , Humans , Male , Time Factors
10.
Neurosci Lett ; 239(2-3): 121-4, 1997 Dec 19.
Article in English | MEDLINE | ID: mdl-9469671

ABSTRACT

The electroencephalogram (EEG) of nine healthy individuals was recorded at half-hourly intervals during approximately 40 h of sustained wakefulness in a constant routine protocol. EEG power density in the 0.75-9.0 Hz range exhibited a global increasing trend, and a local trough in the evening, centered approximately 6 h prior to the temperature minimum. The former could be attributed to a wake-dependent influence, and the latter to a circadian influence. Power density in the 9.25-12.0 Hz band showed a circadian modulation, the trough coinciding with the minimum of the endogenous rhythm of body temperature, whereas a wake-dependent influence was not evident. Power density in the 12.25-25.0 Hz range exhibited a wake-dependent increase, whereas a circadian modulation was absent. It is concluded that the circadian pacemaker and the wake-dependent (i.e. homeostatic) process affect the waking EEG in a frequency-specific manner.


Subject(s)
Brain/physiology , Circadian Rhythm/physiology , Homeostasis/physiology , Sleep/physiology , Wakefulness/physiology , Adult , Electroencephalography , Electromyography , Electrooculography , Female , Humans , Male , Sleep Deprivation/physiology , Sleep Stages/physiology , Time
11.
Am J Physiol ; 270(1 Pt 2): R41-53, 1996 Jan.
Article in English | MEDLINE | ID: mdl-8769783

ABSTRACT

Homeostatic sleep regulation in habitual short sleepers (sleep episode < 6 h, n = 9) and long sleepers (> 9 h, n = 7) was investigated by studying their sleep structure and sleep electroencephalogram (EEG) during baseline conditions and after prolonging their habitual waking time by 24 h. In each sleep episode, total sleep time was > 3 h longer in the long sleepers than in the short sleepers. Sleep deprivation decreased sleep latency and rapid eye movement (REM) density in REM sleep more in long sleepers than in short sleepers. The enhancement of EEG slow-wave activity (SWA; spectral power density in the 0.75-4.5 Hz range) in non-REM sleep after sleep loss was larger in long sleepers (47%) than in short sleepers (19%). This difference in the SWA response was predicted by the two-process model of sleep regulation on the basis of the different sleep durations. The results indicate that short sleepers live under a higher "non-REM sleep pressure" than long sleepers. However, the two groups do not differ with respect to the homeostatic sleep regulatory mechanisms.


Subject(s)
Homeostasis , Sleep/physiology , Adult , Electroencephalography , Humans , Male , Models, Biological , Sleep Stages , Sleep, REM , Time Factors
12.
Neuropsychopharmacology ; 11(4): 237-44, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7857498

ABSTRACT

Electroencephalographic slow-wave activity (SWA; power density in the 0.75 to 4.5 Hz band) and spindle frequency activity (SFA; 11.25 to 15.0 Hz) exhibit a typical time course and a distinct mutual relationship during sleep. Because benzodiazepines (BDZ) suppress SWA and enhance SFA, we investigated the effect of two BDZ-receptor agonists on the dynamics of these EEG parameters. A single dose of midazolam (15 mg), zopiclone (7.5 mg), or placebo was administered before bedtime to healthy young men. Although the two drugs reduced SWA and enhanced SFA, their time course across and within sleep cycles as well as their mutual relationship were little affected. The results constitute further evidence that hypnotics acting as BDZ-receptor agonists do not substantially interfere with the homeostatic aspect of sleep regulation.


Subject(s)
Electroencephalography/drug effects , Hypnotics and Sedatives/pharmacology , Midazolam/pharmacology , Piperazines/pharmacology , Sleep Stages/drug effects , Adult , Azabicyclo Compounds , Humans , Male , Sleep Stages/physiology
13.
Physiol Behav ; 55(4): 769-74, 1994 Apr.
Article in English | MEDLINE | ID: mdl-8190808

ABSTRACT

To investigate the dynamics of heart rate in the course of sleep and to relate cardiac activity to sleep intensity, the electrocardiogram was recorded concomitantly with the polysomnogram in healthy young males. Heart rate was assessed across consecutive non-REM sleep (NREMS)-REM sleep (REMS) cycles as well as within individual episodes of NREMS and REMS. Within a sleep cycle, heart rate was lower in the NREMS episode than in the subsequent REMS episode. A global declining trend was present over successive NREMS episodes and over successive REMS episodes. A rapid increase of heart rate at the NREMS-REMS transitions was followed by a slow decline that started within the REMS episodes. Heart rate variability was higher in REMS than in NREMS and showed an increasing trend over successive REMS episodes but not over successive NREMS episodes. EEG slow-wave activity (spectral power density in the 0.75-4.5 Hz band), an intensity measure of NREMS, declined across NREMS episodes and was not correlated with heart rate. The global trends and ultradian variations of heart rate may represent sleep state-dependent modulations and circadian variations of the autonomic nervous system, which are not fully reflected in the sleep EEG.


Subject(s)
Heart Rate/physiology , Sleep Stages/physiology , Adult , Cerebral Cortex/physiology , Electroencephalography/instrumentation , Fourier Analysis , Humans , Male , Polysomnography/instrumentation , Signal Processing, Computer-Assisted/instrumentation , Sleep, REM/physiology
14.
Psychopharmacology (Berl) ; 114(2): 209-14, 1994 Mar.
Article in English | MEDLINE | ID: mdl-7838909

ABSTRACT

The effect of triazolam (0.25 mg) and placebo was investigated in healthy, male subjects who slept in a sitting position. After the intake of placebo, sleep efficiency, rapid eye movement (REM) sleep and subjective sleep quality were lower than in the preceding sleep episode in bed, while stage 1 and REM sleep latency were higher. Triazolam did not prevent this impairment of sleep. However, in comparison with the placebo condition, the percentage of slow wave sleep was higher in the first third of the night, and in the morning sleep was rated as more quite. EEG power density in nonREM sleep was reduced in the frequency range of 1.25-10.0 Hz and enhanced in the range of sleep spindles (12.25-13.0 Hz). These changes were still present in the last third of the night. In REM sleep, triazolam reduced spectral activity in some frequency bins between 4.25 and 10.0 Hz. The sitting position itself affected the nonREM sleep spectra, since the placebo level in the 2.25-21.0-Hz range exceeded the baseline level. We conclude that a 0.25 mg dose of triazolam does not effectively counteract a posture-induced sleep disturbance, but induces changes in the EEG spectra which are typical for benzodiazepine receptor agonists.


Subject(s)
Electroencephalography/drug effects , Posture/physiology , Sleep Stages/drug effects , Sleep/drug effects , Triazolam/pharmacology , Adult , Arousal/drug effects , Humans , Male
15.
J Sleep Res ; 2(2): 70-81, 1993 Jun.
Article in English | MEDLINE | ID: mdl-10607074

ABSTRACT

The dynamics of the sleep EEG were investigated by all-night spectral analysis of 51 sleep records. Power density was calculated for 1-Hz bins in the 0.25-25.0 Hz range. Values in non-rapid-eye-movement sleep (NREMS) were higher than in REMS in the 0.25-16.0 Hz range, and lower in the 18.25-22.0 Hz range. Power density in the 0.25-12.0 Hz range showed a declining trend over the first four NREMS episodes, which, depending on the frequency bin, could be approximated by non-linear or linear decay functions. In the frequency range of sleep spindles (12.25-15.0 Hz), power density in the 13.25-15.0 Hz band showed an increasing trend between NREMS episode 2 and NREMS episode 4. A correlation matrix of 25 1-Hz bins revealed for NREMS a negative correlation between slow-wave activity (SWA; 0.25-4.0 Hz) and activity in the spindle frequency range. This negative correlation was highest in the first NREMS episode and diminished progressively over the subsequent NREMS episodes. Within NREMS episodes, the values in the spindle frequency range showed a U-shaped time course, the trough coinciding with a high level of SWA. By contrast, in both the early and late part of the episode the two types of activity changed in the same direction. The results are consistent with recent electrophysiological studies indicating that the establishment of NREMS is associated with a progressive hyperpolarization of thalamocortical neurons during which the membrane potential exhibits oscillations first in the spindle frequency range and then in the range of SWA.

16.
Neuropsychopharmacology ; 7(3): 225-32, 1992 Nov.
Article in English | MEDLINE | ID: mdl-1326982

ABSTRACT

A single dose of ethanol (0.60 g/kg of body weight) was administered to eight young healthy male subjects 35 minutes before bedtime. Compared to the average value of two baseline nights, subjective sleep and polysomnographically determined sleep parameters were not significantly affected. In the first 2 hours of sleep after ethanol intake, the combined value of wakefulness, stage 1, and movement time was reduced. In this interval, visually scored stage 4 sleep was increased, and electroencephalographic (EEG) power density in nonrapid-eye-movement (nonREM) sleep was enhanced in the lowest delta frequencies and reduced in the beta range. Computed for the entire sleep episode, power density in REM sleep was enhanced in some theta frequencies. In the sleep episode initiated 24 hours after ethanol intake, power density in nonREM and REM sleep was enhanced in delta and theta frequencies, and the subjectively perceived number of awakenings was reduced. The effects of ethanol on EEG power spectra during sleep differ from those published for benzodiazepine and nonbenzodiazepine hypnotics. This indicates that the effects of ethanol on the human sleep EEG are not mediated by the benzodiazepine receptor.


Subject(s)
Electroencephalography/drug effects , Ethanol/pharmacology , Receptors, GABA-A/drug effects , Sleep/drug effects , Adult , Analysis of Variance , Humans , Male , Reaction Time/physiology , Signal Processing, Computer-Assisted , Sleep/physiology , Sleep Stages/drug effects , Sleep Stages/physiology
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