Sleep research online: SRO

Narcolepsy-Cataplexy (NC) is a neurological disorder associated with the human leukocyte antigen HLA DR2. This is a prerequisite for the disease in 95 to 98% of Caucasian patients. It has been demonstrated that the HLA DQB1*0602 allele is a better marker for narcolepsy than DRB1*1501 (DR2). We present a DR-negative and DQB1*0602-positive Caucasian Spanish patient with a very unusual genotype. A 20-year-old male presented with a 12-year history of excessive daytime sleepiness and sudden muscle weakness caused by laughter and disturbed nocturnal sleep. He had never presented hypnagogic hallucinations or sleep paralysis. The family history was negative. Physical and neurological examinations were normal. The Epworth Sleepiness Scale score was 21/24, The Ullanlinna Scale score was 20/40. The polysomnographic recording showed short sleep latency, increased percentage of stage 1 (St 1), increased number of body movements and decreased sleep efficiency index. MSLT data: mean sleep latency of 1 minute and three sleep onset rapid eye movement (REM) periods (SOREMPs). HLA phenotype: A1, A11; Cw5, Cw7; B44, B39; Bw4, Bw6; DR4, DR8; DR53; DQ6, DQ8 and at the gene level: DRB1*0402, DQB1*0302; DRB1*0806, DQB1*0602. The DRB1*0806 and DQB1*0602 genotype is very infrequent in NC and identical to one African-American case in the series by Mignot et al. (1997a), and to a Caucasian case in another series by Mignot et al. (1997b). This indicates the genetic heterogeneity of the NC.
The time-courses of power in the different frequency bands (1-40 Hz) within the non-rapid-eye-movement (NREM) episode of the human sleep electroencephalogram have provided for many years a fascinating window into the sleep process. Here our analysis of the slow-wave band (1-4 Hz) reveals a hitherto unrecognized very slow oscillation of power with mean period ~15 minutes, an instability that appears to be an integral characteristic of the early NREM episode. The neuronal transition probability (NTP) model has already given a mechanism explaining how power in the spindle band peaks consistently before that of slow wave activity. Here we show that an extension of the model, with the hypothesis of a population of sleep neurons alternating between two steady probability states, can simulate the very slow oscillation. In doing so it gives not only the time course of power in the slow wave band, but also the simultaneous time-courses in the spindle and in the fast frequency bands. Animal data suggest that a brainstem neuronal population, toggled by an external switching source, generates these time-courses and dictates them to the thalamus and thence to the cortex. The discovery of the very slow oscillation and the success of the NTP model in interpreting the overall NREM structure may have important implications for both clinical and fundamental sleep research.
It is a common belief that sleep deprivation increases the susceptibility to diseases. In order to evaluate the effects of sleep deprivation on immune profile in humans, peripheral venous blood was obtained from sixteen healthy young male volunteers. Ten of the volunteers underwent 48 hours of sleep deprivation and the other six maintained their regular sleep schedule and acted as controls. The first blood samples were taken at the end of the first polysomnographic recording at 8:00 a.m. After this sampling, ten subjects were sleep deprived for 48 hours in sedentary conditions. The second and third blood samples were taken at the 24th and 48th hours. The subjects were recorded again to verify rebound effects of sleep deprivation after the third blood sampling. In this second polysomnographic recording, all sleep-deprived subjects showed slow wave and REM sleep rebound. The last blood samples were taken at the 72nd hour of study at 8:00 a.m. CD4, CD8, CD5, CD16, CD19 surface antigen positive lymphocyte subsets, serum IgG, IgM, and cortisol levels were assessed in all samples. Our results showed that the proportion of NK cells were decreased during sleep deprivation and returned to normal values after recovery sleep. In the control group, we did not observe any changes in the same direction as the sleep-deprived group.
Amphetamine-like stimulants are commonly used to treat sleepiness in narcolepsy. These compounds have little effect on rapid eye movement (REM) sleep-related symptoms such as cataplexy, and antidepressants (monoamine uptake inhibitors) are usually required to treat these symptoms. Although amphetamine-like stimulants and antidepressants enhance monoaminergic transmission, these compounds are non-selective for each monoamine, and the exact mechanisms mediating how these compounds induce wakefulness and modulate REM sleep are not known. In order to evaluate the relative importance of dopaminergic and noradrenergic transmission in the mediation of these effects, five dopamine (DA) uptake inhibitors (mazindol, GBR-12909, bupropion, nomifensine and amineptine), two norepinephrine (NE) uptake inhibitors (nisoxetine and desipramine), d-amphetamine, and modafinil, a non-amphetamine stimulant, were tested in control and narcoleptic canines. All stimulants and dopaminergic uptake inhibitors were found to dose-dependently increase wakefulness in control and narcoleptic animals. The in vivo potencies of DA uptake inhibitors and modafinil on wake significantly correlated with their in vitro affinities to the DA and not the NE transporter. DA uptake inhibitors also moderately reduced REM sleep, but this effect was most likely secondary to slow wave sleep (SWS) suppression, since selective DA uptake inhibitors reduced both REM sleep and SWS proportionally. In contrast, selective NE uptake inhibitors had little effect on wakefulness, but potently reduced REM sleep. These results suggest that presynaptic activation of DA transmission is critical for the pharmacological control of wakefulness, while that of the NE system is critical for REM sleep regulation. Our results also suggest that presynaptic activation of DA transmission is a key pharmacological property mediating the wake-promoting effects of currently available CNS stimulants.
Adenosine is currently being investigated as a possible mediator of a homeostatic sleep need. Reports from different laboratories suggest that both adenosine A1 agonists and selective serotonin reuptake inhibitors (SSRI) increase deep slow wave sleep (SWS-2) after an interval. In this study, the sleep-wake effects of the adenosine A1 agonist N6-cyclopentyladenosine (CPA) and the SSRI zimeldine are directly compared in the same animals. Since the SWS-2 increase following SSRIs may be secondary to increased adenosine levels during the initially increased waking, it was also investigated whether the adenosine A1 antagonist 8-cyclopentyltheofylline (CPT) would inhibit the SWS-2 increase following the serotonin reuptake inhibitor. Both the adenosine A1 agonist CPA and the SSRI zimeldine increased SWS-2 after an interval. Both drugs increased slow wave activity and decreased 9-20 Hz activity during SWS-2. Both the adenosine A1 antagonist CPT, zimeldine and the two drugs combined initially increased waking and subsequently increased SWS-2 after 2 or 4 h. All treatments increased 2-6 Hz activity in SWS-2 after 2h. Thus, CPT did not antagonize the SWS-2 increase of zimeldine. Based on the sleep and power spectral effects it is suggested that the adenosine A1 antagonist potentiated the zimeldine effect, possibly due to antagonism of adenosine A1 inhibition of serotonin release. The data indicate that the delayed SWS-2 and slow wave activity increases following zimeldine are not due to increased stimulation of adenosine A1 receptors following the initial sleep loss.
Seven adult Sprague-Dawley rats, chronically implanted with standard electrodes to monitor frontoparietal electroencephalographic (EEG) and nuchal electromyographic (EMG) activity, received, under deep anesthesia, unilateral or bilateral microinjections of ibotenic acid in the lateral part of the parafascicular nucleus of the thalamus. Four days after the injections (corresponding to the period of neuronal destruction), obliteration of the oscillatory activity in the theta range was found on the side ipsilateral to the injection, while on the intact hemisphere the rhythm was well developed. The asymmetry between the two hemispheres was particularly evident during REM sleep but was also seen during attentive but immobile alertness. In bilaterally injected rats, the neocortical theta rhythm was abolished on both hemispheres. These results suggest that in freely-moving rats the lateral parafasciculus neurons are part of the network on which the emergence of the theta rhythm relies.
Predominant metabolic transformations of the nucleoside adenosine. SAH-H, S-adenosylhomocysteine hydrolase; 5'N, 5'-nucleotidase; AK, adenosine kinase; AD, adenosine deaminase; R-CH 3 , methylated substrate; HY, homocysteine. 
Blood adenosine metabolism, including metabolites and metabolizing enzymes, was studied during the sleep period in human volunteers. Searching for significant correlations among biochemical parameters found: adenosine with state 1 of slow-wave sleep (SWS); activity of 5'-nucleotidase with state 2 of SWS; inosine and AMP with state 3-4 of SWS; and activity of 5'-nucleotidase and lactate with REM sleep. The correlations were detected in all of the subjects that presented normal hypnograms, but not in those who had fragmented sleep the night of the experiment. The data demonstrate that it is possible to obtain information of complex brain operations such as sleep by measuring biochemical parameters in blood. The results strengthen the notion of a role played by adenosine, its metabolites and metabolizing enzymes, during each of the stages that constitute the sleep process in humans.
Recent work has implicated the hypocretin (orexin) system in the genesis of narcolepsy. In the current study we demonstrate that systemically administered hypocretin-1 (Hcrt-1) produces an increase in activity level, longer waking periods, a decrease in REM sleep without change in nonREM sleep, reduced sleep fragmentation and a dose dependent reduction in cataplexy in canine narcoleptics. Repeated administration of single daily doses of Hcrt-1 led to consolidation of waking and sleep periods and to a complete loss of cataplexy for periods of three or more days after treatment in animals that were never asymptomatic under control conditions. Systemic administration of Hcrt-1 may be an effective treatment for narcolepsy.
Serotonin (5-HT) has a role in regulating behavioral state and controlling the production of ponto-geniculo-occipital (PGO) waves, though the exact mechanism of action is not known. The most prevailing explanation is that 5-HT exerts its influence on behavioral state and PGO waves by inhibiting and disinhibiting cholinergic cells in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT), which have been implicated in their generation. Recent work in rats has demonstrated 5-HT2 receptors on most cholinergic cells in PPT/LDT. We microinfused the relatively specific 5-HT2 agonist, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), the relatively specific 5-HT2 antagonist, ketanserin, and the nonspecific 5-HT antagonist, methysergide, locally into the peribrachial region of PPT in cats and monitored behavioral state and PGO waves. Neither drug significantly affected behavioral state or PGO wave activity. These results suggest that 5-HT2 receptors associated with cholinergic cells are minimally involved in the control of behavioral state and, together with the recent findings of others, suggest that 5-HT may not modulate PGO wave generation via direct action on cholinergic neurons in PPT/LDT, a departure from the long-held but minimally-tested view.
The effect of flesinoxan, a selective 5-HT1A receptor agonist, WAY 100635, a selective 5-HT1A receptor antagonist, and (+/-)pindolol, a mixed beta-adrenoceptor and 5-HT1A/B receptor antagonist, on spontaneous sleep was studied in adult rats implanted for chronic sleep recordings. Drugs were infused directly into the dorsal raphe nucleus (DRN). Direct application of flesinoxan (25.0 and/or 50.0 ng) into the DRN induced a significant increment of REM sleep (REMS) during the second and third 2 h period of recording. On the other hand, microinjection into the DRN of (+/-)pindolol (100.0 and/or 200.0 ng), and WAY 100635 (12.5, 25.0 and 50.0 ng) significantly reduced REMS during the first and/or second 2 h recording period. Our findings support previous studies indicating that microdialysis perfusion of the 5-HT1A receptor agonist 8-OHDPAT into the DRN increases REMS. In addition, they favor the proposal that microinjection of 5-HT1A receptor antagonists into the DRN would suppress 5-HT inhibition and reduce REMS.
The effect of a single nucleotide polymorphism, a glutamine to arginine amino acid substitution in the human Timeless gene (Q831R, A2634G), on diurnal preferences was studied in a random sample of normal volunteers enrolled in a population-based epidemiology study of the natural history of sleep disorders. We genotyped 528 subjects for this single nucleotide polymorphism and determined morningness-eveningness tendencies using the Horne-Ostberg questionnaire. Our results indicate that Q831R Timeless has no influence on morningness- eveningness tendencies in humans.
The present study was designed to investigate the distribution of brainstem neurons projecting to the pontine wave (P-wave)-generating sites in the rat. In six rats, biotinylated dextran amine (BDA) was microinjected into the physiologically identified cholinoceptive P-wave generation site. In all cases, microinjections of BDA in the cholinoceptive P-wave generating site resulted in retrograde labeling of cell bodies in many parts of the brainstem. The majority of those retrogradely labeled cells were in the pedunculopontine tegmentum, pontine reticular nucleus oralis, parabrachial nucleus, vestibular nucleus, and gigantocellular reticular nucleus. The results presented in this study provide anatomical evidence that the cholinoceptive P-wave generation site in the rat receives anatomical projections from other parts of the brainstem known to be involved in the REM sleep-generation mechanism.
This study investigated the effects of a short afternoon nap (<30 min) in the elderly on subjective mood, performance and electroencephalograms (EEG). Ten healthy elderly persons who habitually napped in the afternoon three or more times a week participated in the present study. They participated in two experimental conditions with an interval of more than five days. In the nap condition, the participants went to bed at 13:00 hours and slept for 30 min, whereas they just had a rest while watching television in the no-nap condition. In both conditions, subjective sleepiness, fatigue, performance and EEG activities with eyes opened and closed were repeatedly measured before and after the nap or rest. The nap significantly reduced subjective sleepiness and fatigue in the afternoon. It also improved performance levels and EEG theta, alpha 1 or alpha 2 band activities with eyes opened and closed. These findings suggest that a short afternoon nap is useful for the elderly in maintaining their daytime psychological, behavioral and physiological arousal at an adequate level.
This paper outlines a conceptual model for the regulation of the circasemidian sleep propensity process with emphasis on a possible mechanism of the afternoon "nap zone". It is proposed that the afternoon nap zone is due to increasing sleep propensity after morning wakening (Borb ly's Process-S) being overwhelmed by a light-sensitive SCN-dependent circadian arousal process of the type discovered by Edgar et al., (1993) and currently being identified in its pathways and neurochemistry by Jouvet and colleagues. It is maintained that this arousal process is reflected in the circadian core body temperature pattern, and that under normal entrained conditions the latter does not resemble a sine-wave or skewed sine-wave. Rather it is very asymmetrical in time and somewhat asymmetrical in amplitude. Cosinor type analyses which enforce symmetry in time and amplitude are therefore ill suited to adequately curve-fit the empirical data. The shape of the circadian arousal system was clarified by meta-analyses of data from three laboratories for three conditions: the normal entrained state, the constant routine, and temporal isolation. Under normal entrained conditions for about one-third of the circadian day core body temperature, and therefore the assumed intensity of the circadian arousal system, is below the mesor with the nadir being at about 0500h; and for about two-thirds of the circadian day it is above the mesor with the acrophase on average being at about 2100h. For modeling purposes, the homeostatic process (Process-S) employed the actual data of the Zurich laboratories for night sleep, but altered the equation for the daytime period to ensure an exponential increase after wake-up. Combining these modified processes indicated that the nap zone could be explained, as predicted, by an increasing homeostatic pressure for sleep across the daytime being reversed by the circadian arousal process. This 2-process combination predicted quite well the shape of the entire circasemidian sleep/wake propensity process and can explain the presence of morning sleep inertia without requiring a third process. It would appear that the circadian arousal process can be modified in phase and in amplitude by a number of normal and pathological conditions.
The "immediate-onset"-acting hypnotics (1-2 h after oral administration) (e.g., benzodiazepines) serve as the leading approach and great progress has been made in this century. They are exogenous from artificial synthesis and mainly fit for short-term insomnia. The "gradual-onset"-acting hypnotics (3-5 d after oral administration) are mild and gradually effective, but are very safe and without noticeable side or adverse effects. They are endogenous or endogenous-mimetic from natural isolation. It may serve as a more natural approach for the treatment of chronic or long-term insomnia, which is mainly gradually developed. This approach is especially useful in treating elderly people, whose numbers are rapidly increasing worldwide, especially in the next century. Sleep-Aid Tea (SAT) is a naturally processed Tea consisting of endogenous or endogenous-mimetic sleep-inducing substances isolated from specific natural and edible fruits and plants well known for the treatment of insomnia, e.g., Compendium of Materia Medica (Li, 1596) associated with modern knowledge and isolation technology (Liu, 1990, 1993). SAT is especially fit for the treatment of insomnia in aged people because it is mild, "gradual-onset"-acting (3-5 d after oral administration), natural, safe and without side effects.
Sleep was recorded in congenic F344 albino (c/c) and pigmented (c/+) rats while they were exposed to various light-dark schedules at 10, 50 and 100 lux. In short LD schedules (1:1 and 3:3), both c/c and c/+ rats had similar patterns of NREM and waking in the light and dark. NREM was higher in the light and there was more wakefulness in the dark. These differences were accentuated with increased light intensity. In contrast, substantial effects on REM sleep were seen only in the c/c rats and increased light levels also enhanced these effects. REM sleep in pigmented c/+ rats was virtually unaffected by lighting changes. These results indicate that different systems are involved in regulating sleep-waking and REM sleep responses to light and further that these systems are differentially affected by alleles at (or near) the c locus and/or albinism.
Clinical and Demographic Characteristics of Patients (n 40) with Primary Alcoholism (Means SD) 
Statistical Analysis (ANOVA) of the Course of Sleep Variables under Baseline Conditions and Values of the Pittsburgh Sleep Quality Index (PSQI) during Abstinence (T0: at the Third Week of Hospitalization; T1: 6 Months after Discharge; T2: 12 Months after Discharge) of 11 Patients with Primary Alcohol Dependence Who Remained Abstinent during the 1-Year Follow-Up 
Sleep disturbances of alcoholics while actively drinking and at the beginning of, and during, abstinence were frequently reported. Recently, Gillin et al. (1994) showed that a high "REM sleep pressure" at the time of admission to a 1-month inpatient alcohol treatment program predicted the relapse in nondepressed patients with primary alcoholism at 3 months following hospital discharge. We investigated 24 patients with primary alcoholism after 2-3 weeks abstinence in the sleep laboratory; in 15 of these patients the cholinergic REM sleep induction test (CRIT) with 10 mg galanthamine was performed additionally. In comparison with an age- and sex-matched healthy control group, patients had a heightened "REM sleep pressure" including shortened REM latency and increased REM density. A decrease of serotonergic neurotransmission is proposed as being the neurochemical mechanism to explain the results in alcoholic subjects. Follow-up investigations will clarify whether the sleep abnormalities in alcoholism are state- or trait-markers and whether they are suitable to predict the relapse risk.
Representative example of camera lucida tracings of medial preoptic area neuron. Inset: Enlarged tracings of a small portion to show the dendritic spine. Scale bar: 16.12µm; inset: 4.06µm. 
The experiments were conducted on 24 adult male Wistar rats to find out the alterations in the levels of monoamines and dendritic spine densities in the medial preoptic area and cortex after total sleep deprivation. Noradrenaline was reduced in the medial preoptic area, though there was no significant change in the cortex. Dopamine and serotonin were decreased both in the medial preoptic area and in the cortex. Dendritic spine counts in the medial preoptic area and the motor cortex were increased after total sleep deprivation. Enhanced release of the monoamines and their subsequent breakdown during sleep deprivation could be responsible for the decreased levels of the transmitters. An increase in synaptic activity, resulting in the enhanced release of the transmitters, might be responsible for the increased spine density after total sleep deprivation. Localized changes in noradrenaline levels at the medial preoptic area suggest its involvement in sleep genesis and maintenance, though its possible contribution to other functions like thermoregulation and reproduction cannot be ruled out. As the available literature does not indicate a role for serotonin and dopamine at the medial preoptic area in sleep regulation, these changes may represent their participation in non-sleep functions.
The present study sought to evaluate concomitant alterations of behavioral and sleep patterns of arthritic rats. Rats were implanted with electrodes for polysomnographic recordings and submitted to the model of arthritis by a subcutaneous (s.c.) administration of Freund adjuvant in the posterior right paw and saline in the posterior left paw. The SHAM group was injected with saline in both paws, whereas the control group (CTL) was not submitted to any manipulation. Behavioral tests were carried out twice before induction of arthritis, on the second day of arthritis, and once a week afterwards until the eighth week. Body weight, colonic temperature, and measurements of the injured paw were carried out on the same days. Arthritic rats presented a reduction of total sleep time, increased latency to synchronized sleep, augmented number of episodes of synchronized sleep, reduction of sleep efficiency, more stage shifts, and increased total alert time. Moreover, these animals presented a lower pain threshold than control and SHAM animals. This reduction was observed on the second day of arthritis and remained so reduced until the end of the study. The data appear to indicate a relationship between altered sleep pattern and increased pain sensitivity in arthritic rats.
Changes in sleep structure, and especially REM sleep, and in EEG activation were studied in relation to the cholinergic deficit found in Alzheimer's Disease (AD). With respect to sleep architecture, only REM sleep percent was reduced in AD patients compared to controls as a result of a decrease in mean REM episode duration. Different results were obtained in patients with progressive supranuclear palsy (PSP). These results are discussed with respect to the role of brainstem and forebrain cholinergic populations in REM sleep generation in humans. More importantly, it was shown by means of spectral analyses that EEG slowing is much more prominent in REM sleep than in wakefulness in AD. Furthermore, there is a distinct topographical pattern of REM sleep EEG slowing in AD patients which is in agreement with findings from neuroradiological and neuropathological studies. Using the ratio of slow over fast frequencies from the temporal regions, a correct classification of 90.4% of subjects was obtained for the REM sleep EEG. This discrimination rate is the best marker of AD so far using a single measure. Quantitative REM sleep EEG was also used to evaluate patients' biological response to cholinergic treatments. Finally, we present here preliminary data on the progression of EEG slowing in wakefulness and in REM sleep. After six months on a placebo, there was only a decrease in alpha activity in wakefulness over all regions studied. No changes were observed for REM sleep.
Visually scored delta activity (stages 3 and 4, SWS) as well as computerized delta activity measures increase after total and selective sleep deprivation. It is, however, still controversial if SWS amount is only a function of prior waking duration, or if it is related to the structure of the previous sleep period (i.e., to the time spent in SWS). In order to clarify if the amount of SWS is crucial in determining SWS recovery, we selectively deprived SWS during two nights to assess the presence of a compensatory SWS rebound in the following recovery night. Ten normal males slept for 6 consecutive nights in the laboratory. After an adaptation and two baseline nights (BSL; BSL-A), selective SWS deprivation was accomplished for two consecutive nights (DEP-1; DEP-2), by means of an acoustic stimulation technique. A recovery (REC) night then followed. An almost complete selective SWS suppression during both deprivation nights was achieved. A significant increase of S4 and SWS in the REC as compared to the BSL-A paralleled a significant shortening of S3 and S4 latencies. S2 percentage significantly increased during both DEP nights with respect to the other experimental nights. There was no significant difference among nights with regard to total sleep time, percentage of REM sleep, stage 1, movement time, number of awakenings and number of movement arousals, indicating that the acoustic stimulation technique did not dramatically disrupt normal sleep continuity and architecture. These results indicate that SWS rebound after selective SWS deprivation can be ascribed to the loss of SWS accumulated during two consecutive nights, further supporting the idea that the delta sleep amount is more linked to SWS in the previous sleep periods than to the total sleep duration.
Prolactin administered systemically, intracerebroventricularly or locally into the lateral hypothalamus enhances rapid eye movement sleep (REM) when given diurnally and decreases REM when given nocturnally. The amygdala is being recognized as an important modulator of behavioral state, and the central nucleus of the amygdala (CNA) has a high concentration of prolactin fibers and receptors. We microinjected prolactin (10, 100, 250 ng/0.2 microliter saline) or saline alone into CNA of rats and measured the effect on behavioral state. Prolactin produced a dose-dependent decrease in non-REM (NREM), with the effect becoming significant at the high (250 ng) dose. REM was not significantly affected at any dosage. The results indicate a role for prolactin in CNA in the control of NREM. The results are discussed in terms of the amygdala having a broad role in the regulation of behavioral state.
The present study was aimed to compare in detail the distribution within the rostral ventromedial medulla of Methionin-Enkephalin-immunoreactive neurons with efferent projections to the facial or trigeminal motor nuclei, using a double immunostaining technique in colchicine-treated cats. Following cholera toxin B subunit injections in the facial or trigeminal motor nuclei, we found that respectively 55% and 65% of the medium to large-sized retrogradely labeled cells in the lateral part of the nucleus reticularis magnocellularis were Methionin-Enkephalin-positive. For both motor nuclei, the double-labeled neurons had similar morphology and size and were located exactly in the same area. They could therefore belong to the same population of reticular enkephalinergic neurons. Based on these and previous anatomical and electrophysiological data, we propose that these enkephalin-containing neurons could participate in the hyperpolarization of brainstem and spinal somatic motoneurons during paradoxical sleep.
Our aim was to determine the effects of intrauterine compromise, induced by maternal anemia, on ventilatory responsiveness of the sleeping newborn to progressive asphyxia. We induced anemia in 6 sheep for the final third of pregnancy and studied their offspring for 2-3 weeks after birth. Lambs from anemic ewes were growth-restricted at birth; they and 6 control lambs were chronically instrumented soon after birth and underwent studies during which we determined ventilatory and arousal responsiveness to a progressive asphyxic stimulus during sleep. During quiet wakefulness, active sleep and quiet sleep, lambs from anemic ewes had elevated end-tidal CO2 levels (FECO2,%) compared to controls. Ventilatory responsiveness (i.e., gradient of relationship between minute ventilation and FECO2) was greater in quiet sleep than in active sleep for both groups of lambs but did not differ between the two groups in either active or quiet sleep. Lambs from anemic ewes had significantly higher FECO2 values than controls before arousing from either active or quiet sleep. Other indices of arousability (time to arousal, percent hemoglobin saturation at arousal) were not different between the two groups. Our results indicate that prenatal exposure to maternal anemia induces fetal growth restriction and elevates the CO2 'set-point' for normal ventilation. It does not, however, produce significant abnormalities in ventilatory responsiveness to progressive asphyxia during sleep.
Neurons of the cholinergic mesopontine tegmentum preferentially discharge during REM sleep and are thought to promote this state. It has been hypothesized they are inhibited during wakefulness by serotonergic input. The present study used the microdialysis sampling procedure coupled to microbore HPLC to measure extracellular serotonin levels in the pedunculopontine tegmental nucleus (PPT) in naturally sleeping cats. Extracellular serotonin levels were found to be highest during periods of wakefulness, lower during slow wave sleep, and lowest during periods of REM sleep. During wakefulness serotonin levels (mean A+/-SEM) measured in 10 A microliter samples were 1.14 A+/- 0.13 fmol/sample, whereas during slow wave sleep levels declined significantly to 72% of the wakefulness baseline (0.85 A +/- 0.11 fmol/sample), and dropped further to 45% of the wakefulness baseline in REM samples (0.52 A +/- 0.10 fmol/sample; all p's<0.003). The decrease in PPT serotonin levels during sleep may be an important determinant in the timing of REM sleep cyclicity. The data support the hypothesis that, during slow wave sleep and REM sleep, the declining levels of serotonin release the PPT REM-promoting neurons from serotonergic inhibition, which, in turn, leads to increases in acetylcholine release in terminal areas, facilitating the emergence of REM sleep.
Cellular responses to many extracellular signals occur through phosphorylation or dephosphorylation of intracellular proteins. To determine whether changes in protein phosphorylation accompany the electrophysiological changes occurring during the sleep-waking cycle, immunocytochemical mapping of cells labeled with anti-phosphoserine and anti-phosphothreonine antibodies was performed on brain sections of sleeping and waking rats. Animals implanted for chronic polysomnographic recordings were sacrificed after either 3h of sleep or 3h of sleep deprivation by gentle handling. Anti-phosphoserine and anti-phosphothreonine staining was mainly localized in neurons and was high in some brain regions, such as cerebral cortex and hypothalamus, and low in others, such as the thalamus. In all cases, the number of cells labeled with either antibody in the cerebral cortex was markedly higher in rats sacrificed after 3h of waking than in rats sacrificed after 3h of sleep. Unilateral lesions of the locus coeruleus by local injection of 6-hydroxydopamine were performed in other animals to determine whether the increase in protein phosphorylation during waking was influenced by the activity of the noradrenergic system, which is higher in waking than in sleep. In animals sacrificed after 3h of spontaneous or forced waking, the number of labeled neurons in the cerebral cortex was decreased on the side in which noradrenergic fibers had been lesioned. These results suggest that 1) neurons exist physiologically in different states of phosphorylation, ranging from a state of very high phosphorylation (e.g., in the cerebral cortex) to a state of very low phosphorylation (e.g., in many thalamic nuclei); 2) the fraction of highly phosphorylated neurons in cerebral cortex is higher in waking than in sleep and 3) part of the immunoreactive phosphorylation present in highly labeled cortical neurons is controlled by the locus coeruleus.
Orexin (hypocretin)-containing neurons of the hypothalamus project to brainstem sites that are involved in the neural control of REM sleep, including the locus coeruleus, the dorsal raphe nucleus, the cholinergic zone of the mesopontine tegmentum, and the pontine reticular formation (PRF). Orexin knockout mice exhibit narcolepsy/cataplexy, and a mutant and defective gene for the orexin type II receptor is present in dogs with an inherited form of narcolepsy/cataplexy. However, the physiological systems mediating these effects have not been described. We reasoned that, since the effector neurons for the majority of REM sleep signs, including muscle atonia, were located in the PRF, this region was likely implicated in the production of these orexin-related abnormalities. To test this possibility, we used microdialysis perfusion of orexin type II receptor antisense in the PRF of rats. Ten to 24 hours after antisense perfusion, REM sleep increased two- to three-fold during both the light period (quiescent phase) and the dark period (active phase), and infrared video showed episodes of behavioral cataplexy. Moreover, preliminary data indicated no REM-related effects following perfusion with nonsense DNA, or when perfusion sites were outside the PRF. More work is needed to provide precise localization of the most effective site of orexin-induced inhibition of REM sleep phenomena.
Severity of negative esophageal pressure (Pes) and apnea hypopnea index (AHI) were investigated in 34 patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). The OSAHS patients were diagnostically classified as having obstructive sleep apnea syndrome (OSAS) or upper airway resistance syndrome (UARS). Diagnosis of OSAS was based on an AHI of more than 5, and that of UARS on an AHI of less than 5, EEG arousals which were associated with apnea, hypopnea and/or respiratory effort occurring more than 10 times per hour, and daytime sleepiness. Negative Pes was represented by the greatest peak (NPes Max) and the number of increased (more than 13.5 cmH2O) episodes per hour (NPesI13.5). There was no significant correlation between the AHI and Pes indices, but NPes Max and NPesI13.5 showed significant correlation (p<0.01). NPes Max and NPesI13.5 showed no significant differences among the severe OSAS (AHI>50; 8 cases), moderate OSAS (50>AHI>15; 10 cases), mild OSAS (15>AHI>5; 9 cases) and UARS (7 cases) groups. We conclude that AHI does not reflect the severity of the increase in negative Pes, which is an important aspect of the pathophysiology of OSAHS. Assessment of OSAHS based on AHI alone may therefore underestimate the risk of increased negative Pes in cases with reduced AHI.
We have no information on snoring and obstructive sleep apnea (OSA) in our population, which is predominantly Chinese. Our perception is that sleep apnea syndrome is more common than the 2-4% prevalence (Young et al., 1993) often quoted, judging from the experience in our sleep disorder unit. We studied the snorers in an adult population in Singapore and then went on to see how many snorers suffer pathological apnea and sleep apnea syndrome. Room partners, 220 of them aged 30-60 years, were interviewed for their observation of snoring among each other. 106 consecutive habitual loud snorers of a similar age group in the same population were studied with polysomnography in our sleep laboratory. An apnea index greater than 5 was considered pathological. 24.09% were loud habitual snorers. 87.5% of loud habitual snorers had significant obstructive apneas on the polysomnogram and 72% of these apneics complained of excessive daytime sleepiness (EDS). Given the clinical observation that all apneics snored, by extrapolating these figures, we guess that sleep apnea syndrome affects about 15% of the population. Multiple Sleep Latency Tests validated EDS in our cases with clinical hypersomnia. Hypersomnolence was significantly related to the poor delta wave sleep. Contrary to what was believed, OSA occurred predominantly in stage 1 and 2 non-rapid eye movement (NREM) sleep rather than in REM sleep. The frequent arousals prevented sleep going beyond stage 1 and 2.
The role, if any, of exercise training in the management of individuals with obstructive sleep apnea syndrome (OSAS) is unclear. Anecdotally, patients have reported improvement in symptoms with regular participation in an exercise regime. In this study, we evaluated the effects of an exercise training program and weight loss on physical and subjective measures associated with OSAS. Nine subjects with mild to moderate OSAS completed a six month supervised exercise program. Pre and post-training measures on polysomnographic testing, physical training, anthropometric measures, quality of life (QOL), daytime somnolence and mood states were assessed. A significant decrease in the AHI (p=0.002) was noted along with improvements (p<0.05) in total sleep time, sleep efficiency, number of awakenings/hour, arousals/hour, apnea index and mean exercise training workloads. Significant decreases (p<.001) in weight (-6.2 kg) and body mass index (-1.6) were observed. Evaluation of QOL measures by the Health Status Questionnaire, Profile of Mood States and Epworth Sleepiness Scale showed significant changes in health status, affective state, and a decrease in daytime somnolence. Regular exercise training had a positive impact on the AHI, aerobic capacity, body mass index and QOL. However, exercise training alone was not an adequate intervention strategy for most individuals with OSAS but may serve well as an adjunct treatment strategy in the conservative management of individuals with mild to moderate OSAS.
Muscular pharyngeal structural changes, as fibre type disproportion, have been described in patients affected by Obstructive Sleep Apnea (OSA) and in an animal experimental OSA model. The unsolved question is whether these muscular abnormalities are either secondary to a compensatory increased activity or due to a constitutionally determined reduction of slow-alpha motor neurons. In the present study Medium Pharyngeal Constrictor Muscles (MPCM) of OSA (n = 13) and non-OSA (n = 9) patients have been morphologically evaluated. In addition a needle biopsy of Vastus Lateralis Muscle (VLM) was performed in 5 randomly selected patients of each group. Our results confirmed a specific fibre type disproportion of MPCM of OSA patients compared to non-OSA ones with a type II predominance and aspecific myopathic changes such as fibrosis and central nuclei. No difference was found in the VLM of the two groups. This finding could be explained by a secondary adaptive transformation consequent to nocturnal upper airway resistance in OSA. In fact, it has been demonstrated in human muscle that heavy-resistance training may produce preferential type II fibre hypertrophy in stimulated muscle.
Cluster headaches (CH) frequently recur at the same point in the circadian cycle, often during sleep. They may, in some cases, represent a susceptible individual's response to hypoxemia or other physiological changes induced by obstructive sleep apnea (OSA). If and when this mechanism exists, timing of CH close to the onset of sleep-and therefore OSA-might be expected. We questioned 36 subjects with CH about the times at which their CH usually occurred and about several symptoms known to be predictive of OSA, including habitual snoring, loud snoring, observed apneas and excessive daytime sleepiness. We then used logistic regression to determine whether occurrence of CH in each of six time periods was associated with OSA symptoms. The 23 subjects (64%) who reported CH in the first half of a typical night's sleep also tended to report headaches during the midday/afternoon period. Symptoms of OSA, and in particular habitual snoring, were predictive of both first-half-of-the-night and midday/afternoon CH (p<.05). Thirty-one subjects (86%) reported that their CH were sleep-related, usually occurring during any part of the night or on awakening, but symptoms of OSA were not predictive of this timing pattern. In short, several OSA symptoms showed an association with CH occurrence in the first half of the night but not with sleep-related CH in general. These findings suggest that in some patients, physiological consequences of OSA may trigger CH during the first few hours of sleep and thereby influence the timing of subsequent daytime headaches.
Because Obstructive Sleep Apnea Syndrome (OSAS) patients may be treated for comorbidities prior to OSAS diagnosis, we examined the health care utilization records of 181 OSAS patients and those of matched controls. We compared OSA patient health care utilization for a ten-year interval prior to diagnosis to those of randomized age-, gender-, and geographically-matched controls from the general population. We found that OSAS patients used approximately twice the resources (as defined by physician claims and stays in hospital) in the ten years prior to their diagnosis. Physician claims for cases totaled $686,365 ($3,972 per patient) compared to $356,376 ($1,969 per patient) for the controls for the length of the study. Utilization was significantly higher in 7 of 10 years prior to diagnosis. OSAS patients also had more hospitalizations: they had 1,118 nights (6.2 per patient) in hospital versus 676 nights (3.7 per patient) for controls over the ten-year period. Thus OSA patients are heavy users of health care resources ten years prior to diagnosis.
We examined the effects of cervical position on the Obstructive Sleep Apnea Syndrome (OSAS) through the use of a custom-designed cervical pillow which promoted neck extension. Twelve subjects with OSAS were recruited from a tertiary sleep disorder clinic population. Of the twelve subjects, three had mild cases of OSAS, four had moderate cases, and the remaining five had severe cases. The subjects used their usual pillows during two consecutive recorded baseline nights in our laboratory. The subjects then used the cervical pillow for five days at home, and returned for two consecutive recorded nights at our laboratory while using the cervical pillow. During the nights in our laboratory, the subjects completed questionnaires, were videotaped to record head and body position, and had their breathing parameters recorded during sleep. Subjects with mild OSAS cases had a non-significant improvement in the severity of their snoring and a significant improvement in their respiratory disturbance index with the cervical pillow, while subjects with moderate OSAS cases showed no improvement in these parameters. Subjects with severe OSAS cases showed slight improvement in some measures of their abnormal respiratory events during the experimental period.
The 24-hour sleep/wake distributions of untreated patients with narcolepsy-cataplexy and matched normal habitual nappers were compared using home ambulatory monitoring. Subjects followed their usual sleep patterns including, for the habitual nappers, a self-selected daytime nap. There were no differences in 24-hour totals of sleep between groups other than a small increase in SWS in narcolepsy. Narcolepsy showed greater amounts of day sleep (stages 2, SWS, REM and total sleep) and less night sleep (stage 2, total sleep). Data were collapsed into 5 min epochs and entered into a matrix. The data in the two groups were then "wrapped" (re-aligned) around the 24 hours with phase 0 as each of the times of: evening sleep onset, onset of SWS, mid-point of night sleep and moment of morning awakening. In habitual nappers alignment beginning at morning wake-up produced the highest amplitude, least temporal dispersion and greatest kurtosis of daytime sleep (naps). The 24-hour sleep/wake distribution curves of both subject groups (data aligned at morning wake-up) based on collapsed data into 5 min bins then underwent curve fitting using 15th order polynomial regression. As with visual analyses of the raw data, the curve fits confirmed that the peak in daytime sleep propensity in narcoleptics was earlier by about 40 (2.66 hours). It was concluded that decreased daytime amplitude of a circadian arousal system was the most parsimonious explanation for the increased amount, broader temporal distribution and relative phase advance of day sleep in narcolepsy and that, as well, such a mechanism could explain a number of other features of the disease.
This study assessed a proposed sleep-preserving role for sleep spindles by evaluating variations in this activity as a function of factors, both naturally occurring and experimentally induced, known to affect and effect arousal from sleep. These factors included age, auditory stimulation, and experimentally induced arousal from sleep. Analyses were based on data from 84 males (5-49 yrs. old) from normal and clinical (hyperactive, enuretic, and chronic pain) populations who had participated in sleep auditory arousal threshold studies involving adaptation and 1-2 experimental nights. Spindles on experimental nights were visually analyzed and incidence determined for the two minutes preceding and throughout all Stage 2 arousal attempts. Prestimulation spindle occurrence in 39 preadolescent subjects with two experimental nights did not vary significantly from night-to-night, and prestimulation period comparisons between clinical groups and their respective controls were also non-significant. Anticipated relationships between spindle activity and indices of arousal-either inverse with respect to known variations in arousal threshold, i.e., decreases with age and across the night, or direct with respect to stimulus intensity particularly on trials when arousal did not occur-were not observed. Instead, all age groups showed significant decreases in spindle density as an increasing negative function of stimulus intensity. These findings suggest that to the extent to which sleep spindles can be considered to play a role in sleep preservation by inhibiting or attenuating potentially arousing stimuli, these effects appear to be restricted to endogenously generated stimuli and are passive rather than reactive in nature.
We have examined the effect of injection of 6-hydroxydopamine (6-OHDA) into the ventral tegmental area (VTA) on the changes in arterial blood pressure (AP) and heart rate (HR) during the transition from non-rapid eye movement (NREM) sleep to REM sleep. The 6-OHDA-treated rats showed suppression of the increase of AP and HR during REM sleep and of theta frequency in the cortical electroencephalogram (EEG) during wakefulness (W) and REM sleep. It is suggested that midbrain dopaminergic neurons are involved in the control of AP and HR during REM sleep and in the EEG theta activity.
The P1/P50 midlatency auditory evoked potential is a sleep state-dependent waveform present during waking and rapid eye movement (REM) sleep and absent during slow-wave sleep. The P50 potential was studied in normal male and female subjects of various ages including post-pubertal adolescents (12-19 yrs), young adults (24-39 yrs), middle-aged adults (40-55 yrs) and older adults (55-78 yrs). There were no statistically significant differences in the mean peak amplitude or mean peak latency of the P50 potential between males and females or between age groups. Using a paired stimulus paradigm, the degree of sensory gating of the P50 potential was tested at three different interstimulus intervals (ISIs), 250, 500 and 1000 msec. There were no statistically significant differences in the sensory gating of the P50 potential between males and females. However, there was a significant decrease in sensory gating of the P50 potential in the adolescent group compared to each of the other age groups at the 250 msec ISI, but not at the 500 or 1000 msec ISI. These results suggest the presence of decreased sensory gating in normal adolescents compared to normal, older age groups.
Spontaneous awakenings from sleep were studied in a group of 21 elderly subjects (mean age 69.29+/-3.02 years) free of neurological and somatic diseases. The prevalence of awakenings and the duration of waking bouts were analyzed with regard to the prior sleep state. The results showed an increased frequency of awakenings during Stage 2 NREM in the elderly, who wake out of Stage 2 NREM no less frequently than out of REM sleep. This trend is different from that observed in younger subjects (babies and young adults), where a clear prevalence of REM sleep awakenings has been reported. The duration of Stage 2 interrupted by awakening was shorter than Stage 2 followed by sleep. The duration of waking bouts did not differ according to the preceding sleep stage. It is suggested that the relative inability to sustain Stage 2 may be a mechanism which contributes to the difficulty of sleep maintenance in the elderly.
Melatonin treatment has been shown to induce sleepiness and promote sleep in humans. In order to understand the mechanisms by which melatonin acts on human sleep and behavior, it would be useful to have an animal model in which the physiological nocturnal increase in melatonin secretion correlated with nocturnal sleep, i.e., a diurnal species. In this pilot study the oral administration of melatonin to two Pigtail macaques (Macaca Nemestrina) at different times of the day significantly decreased motor activity and promoted earlier sleep onset, as measured actigraphically. The decline in the animals' motor activity occurred within 25-40 min after melatonin ingestion. The duration of motor inhibition was dose dependent. Administration of a 0.05 mg dose induced serum melatonin levels comparable to the peak physiologic concentrations reported in untreated humans and the non-human primates. These data suggest that melatonin may modulate motor activity and sleep pattern in certain diurnally-active primates.
The EEG is desynchronized during wakefulness and REM sleep. There are awake and REM sleep-related neurons in the brain stem. This study was carried out to investigate if the same neuron in the brain stem reticular formation may be responsible for EEG desynchronization during wakefulness and REM sleep. Single neuronal activity was recorded in chronically prepared freely moving normal cats and their activities were correlated with EEG desynchronization during spontaneous wakefulness, REM sleep, and during wakefulness induced by stimulation of the brain stem reticular formation. A majority of the neurons showed an increased firing associated with spontaneous EEG desynchronization during wakefulness and REM sleep, however, about 55% of them showed a similar behavior during stimulation-induced desynchronization. It was found that responses of a majority of the neurons during stimulation-induced desynchronization were similar to that of their firing rate during EEG desynchronization associated with spontaneous wakefulness irrespective of their behavior during REM sleep; the REM-ON neurons were not affected by the stimulation-induced desynchronization. A majority of the neurons which showed an increased firing during spontaneous and stimulation-induced EEG desynchronization received an excitatory input from the brain stem reticular formation. The results of this study suggest that although some neurons may be common, there is a strong possibility that the same neuron in the brain stem reticular formation is not involved in EEG desynchronization during wakefulness and REM sleep.
Using extracellular single unit recording in the medulla of freely moving cats, we have found a population of PS-off ("Type II") neurons that are distinct from the classically described monoaminergic PS-off ("Type I") neurons. The presumed non-monoaminergic Type II PS-off neurons (n=22) showed a relatively high rate of tonic discharge during both quiet waking and slow-wave sleep (10.4+/-4.1 and 9.3+/-3.1 spikes/sec, mean +/- S.D., respectively) and a marked overall decrease in discharge rate during PS (0.3+/-0.4 spikes/sec). In contrast to the presumed monoaminergic PS-off neurons (n=62), Type II PS-off neurons showed short-lasting phasic discharges during PS, often in association with rapid eye movement and PGO wave bursts. These Type II neurons were all characterized by a short action potential which was significantly different from that of the monoaminergic PS-off neurons described so far. Five out of 22 neurons were identified antidromically by stimulation of the ventrolateral reticulospinal tract (vlRST) at the caudal medulla, while 2 of the 22 were identified antidromically by stimulation of the peri-locus coeruleus alpha of the mediodorsal pontine tegmentum. Their mean conduction velocity (7.2+/-1.9 m/sec) was significantly higher than that (0.9+/-0.3 m/sec) of the presumed monoaminergic PS-off neurons which were identified exclusively by stimulation of the vlRST. In addition, when examined during the sleep-waking cycle, the antidromic responses of Type II PS-off neurons were either completely blocked or reduced, with a prolongation of antidromic latency during PS. Most of these neurons were located in medullary structures containing no, or virtually no, monoaminergic neurons, and none responded by inhibition to systemic administration of serotonergic or adrenergic autoreceptor agonists. These findings indicate the existence, in the medulla, of non-monoaminergic PS-off neurons that would play an important role in PS generation.
The interaction of cholinergic and catecholaminergic mechanisms in the mesopontine region has been hypothesized as being critical for the generation and maintenance of active (REM) sleep. To further examine this hypothesis, we sought to determine the pattern of neuronal activation (via c-fos expression) of catecholaminergic and cholinergic neurons in this region during active sleep induced by the pontine microapplication of carbachol (designated as active sleep-carbachol). Accordingly, we used two sets of double-labeling techniques; the first to identify tyrosine hydroxylase-containing neurons (putative catecholaminergic cells) which also express the c-fos protein product Fos, and the second to reveal choline acetyltransferase-containing neurons (putative cholinergic cells) which also express Fos. Compared to control cats, active sleep-carbachol cats exhibited a significantly greater number of Fos-expressing neurons in the dorsolateral region of the pons, which encompasses the locus coeruleus, the lateral pontine reticular formation, the peribrachial nuclei and the latero-dorsal and pedunculo-pontine tegmental nuclei. However, both control and active sleep-carbachol cats exhibited a similar number of catecholaminergic and cholinergic neurons in those regions that expressed Fos (i.e., double-labeled cells). A large number of c-fos-expressing neurons in the active sleep-carbachol cats whose neurotransmitter phenotype was not identified suggests that non-catecholaminergic, non-cholinergic neuronal populations in mesopontine regions are involved in the generation and maintenance of active sleep. The lack of increased c-fos expression in catecholaminergic neurons during active sleep-carbachol confirms and extends previous data that indicate that these cells are silent during active sleep-carbachol and naturally-occurring active sleep. The finding that cholinergic neurons of the dorsolateral pons were not activated either during wakefulness or active sleep-carbachol raises questions regarding the synaptic mechanisms of activation of these cells during these behavioral states.
From the accumulated results, we hypothesize that neurons in the central processor systems of the brain generally exhibit a common state-dependency in slow dynamics of their spontaneous activities during sleep. In this paper, activities of relay cells in the cat's lateral geniculate nucleus (LGN) were studied to see if our hypothesis can be applied in this thalamic region. Data segments in polygraphically steady states were strictly extracted in order to sample the activities whose stationarity was guaranteed in a statistical sense. During slow wave sleep (SWS), the discharge pattern was characterized by short bursts. In contrast, the rather tonic discharge pattern was observed to prevail during rapid eye movement (REM) sleep. Spectral analyses showed white noise-like spectra in the low frequency range of 0.04-1.0 Hz during SWS, and 1/f noise-like spectra in the same frequency range during REM sleep. This state-dependency of the slow dynamics was consistently characterized by the other statistical parameters concerning the second-order moment as well. In contrast, the fast dynamics over 1.0 Hz tended to exhibit neuron-specific changes associated with the sleep state in terms of the Markovian dependency analysis. Consequently, our working hypothesis was not rejected for the LGN relay cells. The result here extends the possibility that the state-dependency of the slow dynamics we found is a general rule concerning single neuronal dynamics in widespread areas of the brain during sleep. The state-dependency of the slow dynamics of the LGN relay cells could be understood according to the proposed mechanism that a state-associated alteration in the global biasing input to a neural network during sleep induces the phenomenon with which we are concerned. The slow dynamics of neuronal activities might provide a novel framework defining SWS and REM sleep states instead of the polygraphic characteristics.
In the transition from NREM to REM sleep, as in other instances of brain activation, a marked increase in cerebral blood flow and glucose uptake is observed, together with a lesser increase in O2 uptake. Brain activation also entails an increase in capillary PO2 and lactate production. The hypothesis of saturation of the oxidative machinery was advanced to explain anaerobic glycolysis and lactate production in the presence of high PO2, but data are available that cannot be explained by this hypothesis: hypoxic spots exist in the brain, augmenting in arterial hypoxia and disappearing in arterial hyperoxia, while tissue [H+] lowers as arterial PO2 increases beyond 100 mmHg. Additional hypotheses are thus required. We suggest that O2 diffusion limitation exists in the brain: microregions lying at mid-distance between capillaries may become hypoxic and partly resort to anaerobic glycolysis. These microregions are thought to enlarge with increasing metabolic rate or arterial hypoxia and give rise to vasodilatatory signals regulating local blood flow. REM sleep time is strongly reduced by hypoxic and increased by hyperoxic atmosphere, in accordance with the existence of an O2 diffusion limitation. Any pathological decrease in arterial PO2 and/or O2 delivery creates a specific risk in REM sleep.
Night sleepiness in two groups of student volunteers who stayed awake for one night was assessed at standardized time (22:00, 01:00, 04:00, 07:00) by the Stanford Sleepiness Scale (SSS). One group (N=21) chewed the chewing gum from midnight until the end of the experiment in the morning, while the other group (N=43) was not chewing at all. The results show that both groups at the initial assessment at 22:00 were not sleepy, with similar SSS scores. Sleepiness in both groups appeared after midnight, worsening towards the morning. The students who were chewing from midnight assessed their sleepiness as lower than the students who were not chewing, which was more marked at 01:00 and 04:00. In the group of medical professionals, nurses and technicians, sleepiness was assessed by SSS in a routine night shift when they, according to their own experience, had the most difficulty overcoming it. Immediately after the assessment they chewed the chewing gum (N=60) or stood/walked (N=27) for 15 minutes. At the end of the fifteenth minute, they assessed their sleepiness again. After 15 minutes of treatment both groups of medical professionals assessed their sleepiness as relieved, with a lower SSS score, more markedly in the chewing group. The obtained results seem to indicate that chewing may alleviate sleepiness in professionals and nonprofessionals who stayed awake through the night.
In order to study both the prevalence of Primary Sleep Disorders (PSD) and sleepiness, and their association to the Chronic Fatigue Syndrome (CFS), 46 unselected outpatients (34 women, mean age 36.5) were examined clinically and underwent two nights of all-night polysomnography and multiple sleep latency tests (MSLT). Forty-six percent presented with a Sleep Apnea/Hypopnea Syndrome Index (AHI>=5), 5% with a Periodic Limb Movements syndrome. No subject received a diagnosis of Narcolepsy or Idiopathic Hypersomnia. Thirty percent showed the presence of objective sleepiness as measured by MSLT<10 minutes. Objective and subjective measures of sleepiness were not associated with CFS, nor with the double diagnosis of CFS and a PSD. The presence of PSD or sleepiness was not associated with any of the clinical scales that were used to measure anxiety, depression, somatisation, physical or mental fatigue, or functional status impairment. Fifty-four percent of CFS patients had no PSD, and 69% no sleepiness. These patients could not be distinguished clinically from patients having a PSD or from those with sleepiness. Therefore, it is unlikely that CFS is simply a somatic expression of any PSD observed in our sample or of sleepiness per se.
The cellular substrates of sleep oscillations have recently been investigated by means of multi-site, intracellular and extracellular recordings under anesthesia, and these data have been validated during natural sleep in cats and humans. Although various rhythms occurring during the state of resting sleep (spindle, 7-14 Hz; delta, 1-4 Hz; and slow oscillation, <1 Hz) are conventionally described by using their different frequencies, they are coalesced within complex wave-sequences due to the synchronizing power of the cortically generated slow oscillation (main peak around 0.7 Hz). In intracellular recordings from anesthetized animals, the slow oscillation is characterized by a biphasic sequence consisting of a prolonged hyperpolarization and depolarization. Basically similar patterns are observed by means of extracellular discharges and/or field potentials in naturally sleeping animals and humans. The depolarizing component of the slow oscillation is transferred to the thalamus where it contributes to the synchronization of spindles over widespread territories. The association between the depolarizing component of the slow oscillation and the subsequent sequence of spindle waves forms what is termed the K-complex. The slow oscillation also groups cortically generated delta waves. At variance with previous assumptions that the brain lies for the most part in the dark and a global inhibition occurs in resting sleep, cortical cells are quite active in this behavioral state. This unexpectedly rich activity raises the possibility that, during sleep, the brain is occupied to specify/reorganize circuits and to consolidate memory traces acquired during wakefulness.
Digitized oscilloscope tracing of a typical Ventral Tegmental Area dopaminergic neuronal spike discharge, recorded extracellularly in an anesthetized rat.
The effect of gamma-hydroxybutyrate (GHB) administration on spontaneously active dopaminergic cells of the ventral tegmental area (VTA) was determined using extracellular single unit recordings in urethane-anesthetized rats. High doses (160-250 mg/kg, i.p.) of GHB reversibly decreased firing rate in 63.6% of the cells tested (n=11); remaining cells (36.4%) were unaffected. When the GHB receptor antagonist NCS-382 (10 mg/kg, i.p.) was co-administered with GHB at high doses, 50% of the cells became excited while remaining cells were unaffected. Of the 34 cells tested with GHB at low doses (10 mg/kg, i.p.), 21 (61.8%) changed their firing activity. Of these, 12 (57.1%) were excited, five (23.8%) were inhibited, and four (19.0%) were first excited then totally inhibited (E/Ipattern). Out of the three E/I cells tested, two resumed their firing activity after apomorphine (50 microgram/kg s.c.), showing that they were in a state of depolarization inactivation. When NCS-382 (10 mg/kg, i.p.) was co-administered with GHB at low doses, only two of the seven cells tested (28.6%) changed their firing activity, both with excitations. We conclude that only low doses of GHB selectively activate GHB receptors. Mechanisms by which low doses of GHB facilitate REM sleep are discussed.
Dorsal mesopontine cholinergic neurons control rapid eye movement sleep (REMS) and wakefulness and contain nitric oxide (NO) synthase. To assess whether local inhibition of NO synthase has distinct effects on sleep, N-nitro-L-arginine methyl ester, an NO synthesis inhibitor (L-NAME, 80 mM), carbachol, a cholinergic agonist (2, 10 or 50 mM), or saline were microinjected (120-200 nl) into the dorsal mesopontine tegmentum in rats. Sleep-wake cycles were monitored during the subsequent 6 h periods. Compared to control injections, L-NAME changed the pattern of REMS by prolonging individual episodes with a small increase in the percentage time of REMS and no change in slow wave sleep (SWS). Carbachol, at 50 mM, enhanced wakefulness and suppressed both SWS and REMS, especially during the first 2 h post-injection. At the two lower concentrations, carbachol moderately enhanced REMS 2-6 h post-injection by increasing the frequency, rather than duration, of individual episodes. Thus, a reduced NO release in the dorsal pontine tegmentum has a powerful consolidating effect on REMS episodes, whereas the direction of the effect of carbachol on the amount of sleep, and REMS in particular, depends on the magnitude of cholinergic stimulation. The REMS-consolidating effects of NO synthase inhibition in the pons may result from modulatory effects of NO on the release of acetylcholine and other neurotransmitters within the dorsal mesopontine tegmentum.
Top-cited authors
Christian Cajochen
  • Universitäre Psychiatrische Kliniken Basel
Derk-Jan Dijk
  • University of Surrey
Florin Amzica
  • Université de Montréal
Shochi Nishino
  • Hirosaki University
Zerrin Pelin
  • Hasan Kalyoncu University