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.

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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.

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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.

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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 µg/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.

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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 15^th 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.

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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 (Borbély'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.

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