EEG spectral activity during paradoxical sleep: further evidence for cognitive processing.

Paradoxical sleep (PS), in which periods with (phasic) and without (tonic) rapid eye movements are intermingled, is hypothesized to be related to cognitive processing and dreaming. Based on polysomnographic data from 12 healthy subjects, this study focuses on the spectral differentiation between phasic and tonic periods. Phasic PS periods exhibited decreased theta and alpha power in the posterior brain areas suggesting the interference of visual processing related to dream imagery. Phasic PS periods were also characterized by a shift from beta to gamma activity in frontal, central and occipital areas reflecting specific phasic related activation. Together, these findings bring new evidence for the existence of visual imagery and cognitive processing during phasic PS.

Brainstem origin for a new very slow (1mHz) oscillation in the human non-REM sleep episode.

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.

Spectral characteristics of sleep EEG in chronic insomnia.

To determine whether the spectral characteristics of the sleep electroencephalogram (EEG) of insomniacs differ from that of healthy subjects, we compared in each of the first four non-rapid eye movement (NREM) and rapid eye movement (REM) episodes: (a) the time courses of absolute power, averaged over the subjects in each group, for the delta, theta, alpha, sigma and beta frequency bands; (b) the relationship between these time courses; and (c) the overnight trend of integrated power in each frequency band. The results show that NREM power, for all frequencies below the beta range, has slower rise rates and reaches lower levels in the insomniac group, whereas beta power is significantly increased. In REM, insomniacs show lower levels in the delta and theta bands, whereas power in the faster frequency bands is significantly increased. Thus, the pathophysiology of insomnia is characterized not only by the generally acknowledged slow wave deficiency, but also by an excessive hyperarousal of the central nervous system throughout the night, affecting both REM and NREM sleep. This hyperarousal is interpreted in terms of the neuronal group theory of sleep which provides a possible explanation for the discrepancies observed between subjective impressions and objective measures of sleep. Also, it is suggested that the progressive hyperpolarization of the thalamocortical neurons as sleep deepens is slower in the patient population and that this may explain the observed slow wave deficiency. The homeostatic control of slow wave activity, on the other hand, would appear to be intact in the patient population.

A neuronal transition probability model for the evolution of power in the sigma and delta frequency bands of sleep EEG.

Although the time-courses of power in the delta and sigma frequency bands over the NREM episode in the human sleep EEG have been studied for several years, and their detailed forms have been well measured, no mathematical model has yet been formulated to account for the relation between them. The model presented here attempts to explain the form and relative timing of these curves by a consideration of the behavior of the thalamocortical neuronal populations that are believed to play a part in their generation. The model applies the mathematics of the cascade radioactive decay process, adapted to a finite population of thalamocortical neurons oscillating initially in the beta mode. At the beginning of the NREM episode, each neuron of this population is assumed to acquire a constant probability of transitionning to the sigma oscillation mode and, at the same time, each neuron of the newly created sigma population is assumed to acquire a constant probability of transitionning to the delta oscillation mode. This simple model is sufficient to explain the main characteristics of the first half of the time-courses of the sigma and delta powers: the initial positive correlation as they increase together, followed by the sigma peak and the subsequent negative correlation. At the end of this first phase, the model initiates an identical, but reverse, process that reproduces the observed delta maximum and sigma plateau, followed by the concomitant fall of both sigma and delta power. The time-course of the beta power and the overall negative correlation between beta and delta are also reproduced as integral consequences of the model.

Effects of nisoxetine, a selective noradrenaline transporter blocker, on sleep in rats.

Nisoxetine has been shown to block specifically noradrenaline (NA) reuptake. Therefore, this potential antidepressant is a valuable tool for investigating the involvement of the NA system in sleep regulation. This study aimed to investigate the effects of different doses of nisoxetine on sleep parameters in rats. The main effects were observed with the highest dose and concern paradoxical sleep (PS). Indeed, although total sleep time was not modified, PS appeared later and its amount and the number of its episodes were reduced. These changes suggest a critical involvement of NA in the induction of PS.

Evolution of delta activity within the nonREM sleep episode: a biphasic hypothesis.

The time course of delta activity within nonREM (NREM) episodes is measured for 24 healthy subjects with normal REM latencies. The first two NREM episodes in particular, show two very clearly separated peaks for about 35% of the subjects. Another 25% show two less well separated peaks. These double peak patterns are also prevalent in the literature, but there has been a tendency to dismiss them as a skipped REM effect. They are, however, still evident even when the data are averaged over the 24 subjects, indicating a systematic phenomenon. These averaged data are well fitted by an analytic function given by the sum of two consecutive overlapping Gaussian curves. The well-behaved residuals also, are an indication that a biphasic model of this kind is statistically appropriate. The model proposed is simple, with parameters related to physiological phenomena, and it suggests that there may be an underlying process with delta waves emanating from two separate signal sources. Recent neurophysiological findings suggest that delta oscillations are generated both in the thalamus and in the cortex and show that excessive synchronization of slow oscillations may lead to seizures. Hence the speculation that the biphasic process may emanate from cortical and thalamic sources and be protective in the sense that it permits smaller delta amplitudes at each source while retaining the integral delta energy necessary to satisfy sleep pressure. It is significant that the two peaks are most evident in the first two NREM episodes where delta power is high.

Relationship between the time courses of power in the frequency bands of human sleep EEG.

The time course of the different frequency bands in the human sleep EEG spectrum within separate NREM and REM episodes averaged over 24 healthy subjects is measured and plotted with the aim of studying their inter-relationship and also the particularities of the beta band. In NREM, a negative sigma-delta cross-correlation corresponding to that expected from neurophysiological data, is found only in the central zone of each episode. The overall correlation is found to be negligible. A neurophysiological explanation is proposed to account for some aspects of this sigma-delta relation. Below the beta frequency range in NREM, the sequence of build-up in power for the different frequencies is from fast to slow, suggesting that there may be a smooth progression in the frequency of oscillation of the thalamocortical neurons depending on their degree of polarization. The beta band is the only one showing a reciprocal relationship with delta throughout the NREM episode, and it is the only one not declining in the REM episode. These differences, together with the close similarity of the beta evolution with that of the REM-on neuronal activity, suggest that beta could directly reflect this activity.

Subjective assessment of sleep: statistical analysis in a population of healthy subjects.

A principal components analysis was carried out on subjective data obtained from the sleep questionnaire systematically used in our laboratory on the morning following a polysomnographic recording. This technique, based on 70 healthy subjects, revealed three principal axes which explore the questionnaire. The first axis reflects the subjective evaluation of the quality of sleep. The second underlines the importance of dreams and of the brief waking periods which immediately follow. Finally, the third axis brings out the subjective assessment of sleep efficiency. The third axis was the most ambiguous and the only one to show a gender difference. Women tend to better estimate general sleep events, while men tend to evaluate better the more circumstantial events. Finally, given the results, it would be interesting to apply a similar analysis to populations presenting sleep disorders in order to establish the presence of an eventual pattern specific to the disorder.

New variables for defining sleep continuity.

One very synthetic way to represent a night's sleep is by way of a hypnogram: a graphical representation of the sleep stages as a function of time. The hypnogram is generally quantified by a series of variables that measure the durations and latencies of the various sleep stages including wake. These variables, however, do not fully account for all the information contained in the hypnogram, in particular information on sleep continuity. A series of variables that measure and localize disruption of this continuity are proposed and their utility validated on three groups of patients presenting sleep disorders. Utility is established if the variable is capable of differentiating between patients and healthy controls. Two sets of variables are examined: those that use the entire sleep period as unit of measurement, and those that are measured within each consecutive NREM-REM sleep cycle. The results show that the variables proposed are able to differentiate between groups and, therefore, are useful measures reflecting the hypnogram more precisely. They also show that fragmentation of REM sleep does not present a systematic trend across the night, but that fragmentation of NREM sleep goes up linearly.

The EEG of the sleep onset period in insomnia: a discriminant analysis.

A period of rapid change in the wave components of the electroencephalogram (EEG) marks the transition from wake to sleep. Twenty-six insomniac and 28 control nights were studied in a discriminant analysis to determine whether this transitional state is modified in any way in subjects diagnosed for psychophysiological insomnia. A discriminant function was derived based on 20 insomniac and 22 normal nights. All 42 nights were correctly classified by this function. The sleep onset period, extending on the average over about 3 minutes, was characterized essentially by the beta and delta components of the EEG signal and by an activity index given by the ratio beta/delta, measured at the temporal lobe sites. Other variables included the subject's age and the magnitude of the changes occurring in the difference between activities in the right and left hemispheres. The variables contributing most to the discrimination were the activity index and beta, especially at the transitions from wake to stage 1 and from stage 1 to stage 2. The contribution of delta to the discrimination was less, but extended further in time to include stage 2 sleep. A test on the remaining six insomniac and six control nights gave a 75% classification accuracy, thus validating the derived discriminant function.

A study of the interrupted REM episode.

Brief interruptions of REM sleep are considered to be part of the REM episode. The maximum allowable duration of such an interruption, which is used to define the end of the REM episode, is currently a matter of debate. Making measurements on individual REM cycles, inter-REM interval analysis was carried out to determine whether the generally adopted 15 minute empirical rule for this maximum needs to be extended to 25 minutes as suggested by several including Kobayashi et al. Our results show that there is no reason to alter the 15 minute rule and that measurements which do not take into account the time-of-night effect may be misleading. The proportion of interrupted REM episodes observed in our population of healthy adults is high. We have therefore also examined in some detail the phenomenology of the temporal evolution of the structure and content of the interrupted REM episodes. Both showed a definite change over the night: the interruptions in the earlier episodes tend to return the system to slow wave sleep while those in the later episodes tend to return it to wake. It is hypothesized that these interruptions reflect a measure of REM sleep pressure and its interaction with both slow wave sleep and wake pressures.

The intrasleep relationship between wake and stage 4 examined by transition probability analysis.

The relationship between wake and stage 4 of slow-wave sleep (SWS), in particular the previously observed deficiency in SWS accompanying sleep containing long-wake periods, is examined in this study of 147 health subjects. Stage shift comportment is compared between those NREM/REM cycles with wake periods greater than 3 minutes and those with less, using the method of transition probabilities. It is shown that these long wake interruptions occur preferentially in light sleep, and systematically disrupt the regular normal descent towards SWS, but do not significantly reduce the number of SWS episodes. There is at the same time, however, a reduction in the average duration of stage 4 periods of SWS which accounts for the observed reduction in the total amount of SWS.

Internal structure of sleep cycles in a healthy population.

A large body of data has been gathered on the sleep characteristics of normal subjects. The evolution of each sleep stage within each NREM/REM cycle is presented in detail, showing stage intensities minute by minute. There is a three-phase pattern in each stage intensity diagram: an initial phase of rapid change; a central phase of relative stability; and a terminating phase, again, of rapid change. The details of this pattern change progressively during the night. Throughout all cycles, there is a complementary relationship between the intensities of stage 2 sleep and the other stages that underlines the central role of stage 2 sleep in all stage transitions. Stage intensity diagrams for two groups, one group with and one group without stage 4 sleep, were compared. Subjects without stage 4 sleep tended to have a shorter duration and greater latency of stage 3 sleep. Surprisingly, cycles interrupted by abnormally long periods of continuous wake showed a negative correlation between the intensities of wake and slow wave sleep, and these interruptions did not appear to reset the cycle clock to zero. Sleep stage intensity diagrams may be useful to study the sleep patterns of populations of insomniac and depressive patients, as well as the effect of drugs on sleep.

Increased frequency of DR2 in patients with aplastic anaemia and increased DR sharing in their parents.

68 patients with aplastic anaemia, their parents and healthy siblings were typed for HLA-A, B and DR antigens. Among the patients there is an overrepresentation of DR2. The parents of affected children show an increased compatibility at the DR locus. This situation could favour the expression of recessive gene(s) involved in haematopoiesis and located in the HLA locus.

Statistical description and evaluation of the interrelationships of standard sleep variables for normal subjects.

This study explores the relationships between the standard sleep variables, particularly between those of NREM and REM sleep. A total of 399 nights of sleep was recorded in 147 adults who had no known pathology. This amount of data allowed for an accurate description of the generally nonnormal variable distributions and established the relative predominance of the intra- over the interindividual variability. Most correlations between variables were low, showing that there is little redundancy in the choice of variables. The relationships between stage 2 and 4 of NREM and REM sleep and between sleep stages and wakefulness were statistically significant. We found that a short latency of stage 2 predicted a sleep of poorer quality than did a longer latency and confirmed that stage 2 has a central role in transition between stages. Finally, there was an association between the variables describing sleep stability and those describing cyclic organization and sleep efficiency. However, it cannot be determined from these data whether teh relationship is causaL or permissive. In addition, these results suggest that further work on cycle structure is required and that future experiments should incorporate a larger number of observed nights per individual.

The effects of indalpine--a selective inhibitor of 5-HT uptake--on rat paradoxical sleep.

In order to document the role of monoamines in the reduction of paradoxical sleep by antidepressant drugs, we examined the effect of indalpine , a selective inhibitor of serotonin uptake. Indalpine dose dependently decreased paradoxical sleep and delayed its first appearance. Pretreatment with parachlorophenylalanine markedly decreased the effect of indalpine . In contrast, pretreatment with alpha-methylparatyrosine potentiated the indalpine -induced depression of paradoxical sleep. The results of the study indicate that the increase of extracellular concentration of 5-HT has an inhibitory effect on paradoxical sleep, and this effect is enlarged if catecholaminergic activity is reduced.

Evidence for HLA-linked susceptibility factors in childhood leukemia.

To test the hypothesis that susceptibility to leukemia can be governed by (a) recessive gene(s) associated with the major histocompatibility complex (MHC) in man, we performed an analysis of the inheritance of HLA antigens in 55 families in which one of the children developed ALL. We found among the parents of affected children a highly significant increased compatibility at the DR locus (p = 0.003). A similar increase was observed in sharing HLA antigens of the B locus (p = 0.02). The observed number of homozygotes among the patients was twice the expected value in families where the parents shared a B and a DR antigen. In segregation analysis, heterozygotes for the shared parental HLA antigen were significantly more prevalent among the healthy siblings. Our genetical analysis indicates that mating of certain shared alleles of the HLA system (especially of the DR locus) is associated with the risk for the offspring to develop ALL in childhood. This situation favors the expression of recessive genes associated with the MHC, and presumably those involved in the susceptibility to acute leukemia. Because familial leukemia is a rare event, the susceptibility to childhood ALL must also implicate genes outside the MHC and important environmental factors.

[Genetic factors linked to the HLA system conferring increased susceptibility to acute lymphoblastic leukemia in children]. / Mise en évidence de facteurs génétiques liés au système HLA conférant une susceptibilité augmentée à la leucémie lymphoblastique aiguë chez l'enfant.

Inheritance of HLA antigens in 55 families of patients with ALL was analyzed. Significantly increased sharing of DR antigens was observed among the parents of the affected children (p = 0.003). A similar increase was noted in the sharing of HLA-B antigens (p = 0.02). The observed number of DR homozygotes among the patients was twice the expected value in families where the parents shared a B and a DR antigen. Segregation analysis of the shared antigens disclosed significant prevalence of heterozygotes among the healthy siblings, which suggested the occurrence of gametic selection in such families. This study indicates that mating of certain shared alleles of the HLA system (especially of the DR locus) is associated with a risk for the offspring to develop ALL in childhood. Restricted heterogeneity of the parental HLA gene pool favours the expression of linked recessive genes and, presumably, of those involved in susceptibility to ALL.