Mullington J, Hermann D, Holsboer F, Pollmächer T. Age-dependent suppression of nocturnal growth hormone levels during sleep deprivation. Neuroendocrinology. 1996;64 (3) :233-41.Abstract
Although the major daily peak in plasma growth hormone (GH) level normally occurs during the early part of nocturnal sleep, it is known that in about one quarter of young healthy men, peaks in circulating human GH occur before sleep onset. Possible factors associated with these nocturnal peaks were investigated in the absence of sleep, including subjectively defined sleepiness, electroencephalographically defined drowsiness and short lapses into sleep, measures of cortisol and temperature. Healthy men between the ages of 20 and 34 years were studied in a between-subjects design, 16 assigned to a sleep deprivation group, and 16 age matched and assigned to a group permitted to sleep. The average GH peak level in the sleeping subjects was 19.9 micrograms/l (+/- 8.4 SD). In the sleep-deprivation group there was a wide range of nocturnal GH patterns, from no detectable rise to normal nocturnal levels (average peak of 10.5 +/- 10.0 micrograms/l). Within the narrow age range sampled, age, body mass index, temperature and cortisol failed to predict nocturnal GH peak in the sleeping group, but regression analysis found age to be a significant negative predictor of nocturnal GH peak level in sleep-deprived subjects. All sleep-deprived subjects who had peak GH levels over 7 micrograms/l were 24 years of age or less. Subjective sleepiness and electroencephalographically defined drowsiness failed to predict either the peak level of GH during sleep deprivation or the cumulative amount measured across the night. These results suggest that the well-known suppressive effect of sleep deprivation on GH secretion is an age-dependent phenomenon which evolves during early adulthood.
Hinze-Selch D, Mullington J, Pollmächer T. [Clozapine, cytokines, fever and sleep]. Wien Med Wochenschr. 1996;146 (13-14) :311-3.Abstract
In 27 schizophrenic patients we investigated plasma levels of cytokines before the initiation of treatment and after the first, second and sixth week of treatment with the atypical antipsychotic agent clozapine. In addition, we did polysomnographic recordings in one schizophrenic patient prior to, during and following clozapine-induced fever. We found that independently of fever clozapine significantly increased the plasma levels of tumor-necrosis-factor a (TNFa) and soluble interleukin-2-receptor (sIL-2r) which were further increased by fever. Interleukin-6 (IL-6) was increased only together with fever and showed a significant positive correlation with clozapine-induced fever. The sleep recording of the fever night revealed severely disturbed sleep. Possible links between the clozapine-induced release of cytokines and clozapine's effect on night sleep are discussed.
Korth C, Mullington J, Schreiber W, Pollmächer T. Influence of endotoxin on daytime sleep in humans. Infect Immun. 1996;64 (4) :1110-15.Abstract
Administration of endotoxin in the evening has been shown to transiently suppress rapid eye movement (REM) and to promote non-REM sleep in humans. In a single-blind placebo-controlled crossover design, we assessed the effects of Salmonella abortus equi endotoxin administered intravenously in the morning on the primary host response and on daytime sleep by use of a multiple napping protocol in healthy volunteers. The extent of the host response achieved by 0.8 ng of endotoxin per kg of body weight given at 0900 h was comparable to that previously reported to result from the administration of 0.4 ng/kg at 1900 h. However, sleep was only slightly influenced. Endotoxin reduced the amount of REM sleep and increased REM latency. Non-REM sleep amount in the first nap, although not significantly changed, correlated negatively with the individual peak levels of interleukin-6 (r = -0.73, P < 0.05). Subjective tiredness, sleep onset latency, total sleep time, and the amounts of slow-wave and non-REM sleep were not affected by endotoxin throughout the entire experiment. Spectral analysis of the electroencephalogram obtained during non-REM sleep yielded no condition differences. We conclude that endotoxin administration in the morning to healthy volunteers, while activating the host defense to the same extent as a lower dose that has been reported to promote non-REM sleep when given in the evening, does not affect non-REM sleep. REM sleep suppression is, to date, the most consistently reported effect of endotoxin on human sleep.
Pollmächer T, Mullington J, Korth C, Hinze-Selch D. Influence of host defense activation on sleep in humans. Adv Neuroimmunol. 1995;5 (2) :155-69.Abstract
Despite considerable progress in our understanding of the phenomenology of sleep and wakefulness, their regulation and peculiar functions are poorly understood. Recent animal research has revealed considerable evidence for interactions between host defense and sleep. Therefore, it has been hypothesized that host response mediators, mainly cytokines like interleukin-1 (IL-1), are involved in physiological sleep regulation. Furthermore, it has been suggested that sleep, and non rapid eye movement (NREM) sleep in particular, has an immuno-supportive function. In humans, sleep-host defense interactions are just starting to be understood. There is quite good evidence that some viral diseases cause excessive sleepiness. Other infectious diseases induce, however, serious disturbances of the distribution of sleep and wakefulness rather than excessive sleep. In addition, some disorders with excessive sleep, daytime fatigue or disturbed night sleep as prominent symptoms are thought to involve, at least in part, immuno-pathophysiological mechanisms. Experimental settings have only recently been used to elucidate host defense-sleep interactions in humans. The effects of endotoxin, a cell-wall lipopolysaccharide of gram-negative bacteria, on sleep have been tested in different settings in healthy volunteers. Endotoxin transiently suppresses rapid eye movement (REM) sleep independently of the time of the day of administration. Only low doses, given in the evening, promote NREM sleep. Electorencephalogram (EEG) power in higher frequency bands is enhanced during NREM sleep, whereas delta activity is not affected. In rats and rabbits, on the other hand, the effects of endotoxin and of the mediators of its activity on REM sleep are variable. Enhanced NREM sleep is a common finding and most pronounced during the active part of the nycthemeron and, in general, EEG delta activity is augmented. In view of these species differences, hypotheses regarding the underlying mechanisms and the biological significance of host defense-sleep interactions, primarily derived from the results of animal studies, may not entirely fit human physiology. They should therefore be re-evaluated and probably modified, through the use of additional experimental approaches in humans.
Hinze-Selch D, Mullington J, Pollmächer T. Sleep during clozapine-induced fever in a schizophrenic patient. Biol Psychiatry. 1995;38 (10) :690-3.
Broughton R, Mullington J. Chronobiological aspects of narcolepsy. Sleep. 1994;17 (8 Suppl) :S35-44.Abstract
The circadian, circasemidian and ultradian features of sleep-wake patterns in narcolepsy are reviewed with respect to the hypotheses that chronobiological disturbances might either be specific to the condition or contribute to its symptomatic profile. The position is taken that, while there are characteristic temporal features associated with the disorder, the chronobiological system is essentially intact, although quantitatively altered. It appears that the fundamental physiopathogenesis involves state boundary control mechanisms, which operate in state transitions, rather than chronobiological mechanisms affecting the timing of the manifestation of symptoms associated with the disease. We review our recent results from sleep-wake schedule studies designed to improve the maintenance of alertness in narcolepsy-cataplexy and report new analyses of subjective sleepiness data. The schedules employed were designed to take preexisting circadian, circasemidian and ultradian sleep-wake patterns of these patients into consideration.
Mullington J, Broughton R. Daytime sleep inertia in narcolepsy-cataplexy. Sleep. 1994;17 (1) :69-76.Abstract
Eight volunteers with narcolepsy-cataplexy participated in a study of scheduled naps and performance. Sleep inertia was examined following five "short" naps of 5% and a single "long" nap of 25% of total 24-hour sleep time as determined by prior sleep log data. Contrary to some subjective reports, short naps (mean duration of just under 30 minutes) were accompanied by sleep inertia in narcoleptics. As measured by the descending subtraction task, this sleep inertia was at times quite prolonged and lasted 20 minutes after waking from midday short naps, which ended on average at 1555 hours. In addition, sleep inertia, as measured by both the descending subtraction task and the four-choice reaction-time test, was evident throughout both afternoon and evening short naps; however, it was completely absent from reaction-time test results immediately following the single long nap, which ended on average at 1640 hours. Sleep inertia was maximum after slow-wave sleep arousals and was minimal or absent following the first short nap, which also contained the highest amount of rapid eye movement sleep of all naps.
Mullington J, Broughton R. Scheduled naps in the management of daytime sleepiness in narcolepsy-cataplexy. Sleep. 1993;16 (5) :444-56.Abstract
A repeated testing paradigm was used to assess the efficacy for the management of daytime sleepiness in narcolepsy-cataplexy of single long, multiple short and no-nap sleep/wake schedule conditions, with total sleep per 24 hours held constant. Eight narcoleptic subjects participated and followed each experimental schedule for two consecutive days, the second of which served as a test day during which simultaneous electroencephalogram (EEG) polygraphic recordings were made. Performance tests reported here include a grammatical transformation test and a four-choice reaction time test. A single long nap placed 180 degrees out-of-phase with the nocturnal midsleep time improved sustained performance over the no-nap condition. Reaction time performance was significantly improved in the long nap condition over the no-nap condition. Time-of-day analyses found that the greatest improvement was in the afternoon and evening. By contrast, the grammatical transformation test results suffered under the napping compared to no-nap schedules, suggesting that continuity of wakefulness and/or a long nocturnal sleep period may be important for this test. In addition, unscheduled sleep episodes tended to occur earlier in the day than the period of maximum afternoon sleep tendency seen in normal subjects. Two napping strategies are suggested for further study.
Broughton R, Mullington J. Circasemidian sleep propensity and the phase-amplitude maintenance model of human sleep/wake regulation. J Sleep Res. 1992;1 (2) :93-98.Abstract
Evidence for circasemidian sleep/wake regulation is briefly reviewed with respect to protocols used to quantify sleep propensity. Existing models of sleep/wake regulation are examined in view of their ability to accommodate data which demonstrate an afternoon sleep period. Finally, a modelling approach is briefly outlined which emphasizes the maintenance of the phase and amplitude characteristics of the circadian rhythm of body (and brain) temperature and predicts the circasemidian phenomena.
Haack JA, Rivier J, Parks TN, Mena EE, Cruz LJ, Olivera BM. Conantokin-T. A gamma-carboxyglutamate containing peptide with N-methyl-d-aspartate antagonist activity. J Biol Chem. 1990;265 (11) :6025-9.Abstract
Conantokin-T, a 21-amino acid peptide which induces sleep-like symptoms in young mice was purified from the venom of the fish-hunting cone snail, Conus tulipa. The amino acid sequence of the peptide was determined and verified by chemical synthesis. The peptide has 4 residues of the modified amino acid, gamma-carboxyglutamate (Gla). The sequence of the peptide is: Gly-Glu-Gla-Gla-Tyr-Gln-Lys-Met-Leu-Gla-Asn-Leu-Arg-Gla-Ala-Glu-Val-Lys- Lys-Asn-Ala-NH2. Conantokin-T inhibits N-methyl-D-aspartate (NMDA) receptor-mediated calcium influx in central nervous system neurons. This observation suggests that like conantokin-G (a homologous Conus peptide with recently identified NMDA antagonist activity) conantokin-T has NMDA antagonist activity. A sequence comparison of conantokins-T and -G identifies the 4 Gla residues and the N-terminal dipeptide sequence as potential key elements for the biological activity of this peptide.
Purcell S, Mullington J, Moffitt A, Hoffmann R, Pigeau R. Dream self-reflectiveness as a learned cognitive skill. Sleep. 1986;9 (3) :423-37.Abstract
This research was directed toward the contradiction sustained by cognitive dream psychology, which on the one hand regards dreaming as higher symbolic activity and, on the other, sees its organizational and functional characteristics as derivative and/or inferior to those of waking consciousness. Study 1 evaluates the degree of self-reflective meta-cognition in dreams from different sleep stages. Subjects were 24 college students selected such that half were self-reported high-frequency dream recallers and half were low-frequency recallers. Both groups were composed equally of men and women. Greater self-reflectiveness (SR) was found in REM dreams as compared with those from stages 2 and 4, which did not differ. High-frequency recallers showed more dream SR than did low-frequency recallers. Study 2 assessed the extent to which self-reflective and lucid dreaming can be learned as a cognitive skill by varying levels of intention and attention paid to dreaming. After 3 weeks of home dream collection, results showed that four experimental groups had greater dream SR than did a baseline group. The most effective treatment was the mnemonic, wherein attention patterning schemas learned in waking resulted in more self-reflective and lucid dreaming than did either baseline or attention-control conditions. These results provide evidence that dreaming is not single-minded but variable along a self-reflective process continuum, and suggest functional and organizational levels that are consistent with the conception of dreaming as higher order cognitive activity.
Haack HP. [Masked depression]. Dtsch Med Wochenschr. 1985;110 (13) :507-9.