Events In Rapid Eye Movement Sleep Research Articles

Novel Electrophysiological Signatures of Learning and Forgetting in Human REM Sleep.

Despite the known behavioral benefits of rapid eye movement (REM) sleep, discrete neural oscillatory events in human scalp electroencephalography (EEG) linked with behavior have not been discovered. This knowledge gap hinders mechanistic understanding of the function of sleep, as well as the development of biophysical models and REM-based causal interventions. We designed a detection algorithm to identify bursts of activity in high-density, scalp EEG within theta (4-8 Hz) and alpha (8-13 Hz) bands during REM sleep. Across 38 nights of sleep, we characterized the burst events (i.e., count, duration, density, peak frequency, amplitude) in healthy, young male and female human participants (38; 21F) and investigated burst activity in relation to sleep-dependent memory tasks: hippocampal-dependent episodic verbal memory and non-hippocampal visual perceptual learning. We found greater burst count during the more REM-intensive second half of the night (p < .05), longer burst duration during the first half of the night (p < .05), but no differences across the night in density or power (p > .05). Moreover, increased alpha burst power was associated with increased overnight forgetting for episodic memory (p < .05). Furthermore, we show that increased REM theta burst activity in retinotopically specific regions was associated with better visual perceptual performance. Our work provides a critical bridge between discrete REM sleep events in human scalp EEG that support cognitive processes, and the identification of similar activity patterns in animals models that allow for further mechanistic characterization.Significance Statement Current understanding of sleep and its role cognitive processes is incomplete due to a lack of discrete electrophysiological events in human rapid eye movement (REM) sleep detectable via scalp EEG. Our work remedies this gap in knowledge by designing an open-source, computational approach to identify electrophysiological alpha and theta burst events in REM sleep. Additionally, we provide evidence that these burst events are functionally important for learning and memory. Defining burst events in human REM will contribute to the development of a comprehensive mechanistic model of how sleep as a whole, and REM specifically, facilitate cognitive processes, and provide a deeper understanding of the fundamental electrophysiological properties of REM sleep that are distinct from non-REM sleep.

Neural Control of REM Sleep and Motor Atonia: Current Perspectives.

Since the formal discovery of rapid eye movement (REM) sleep in 1953, we have gained a vast amount of knowledge regarding the specific populations of neurons, their connections, and synaptic mechanisms regulating this stage of sleep and its accompanying features. This article discusses REM sleep circuits and their dysfunction, specifically emphasizing recent studies using conditional genetic tools. Sublaterodorsal nucleus (SLD) in the dorsolateral pons, especially the glutamatergic subpopulation in this region (SLDGlut), are shown to be indispensable for REM sleep. These neurons appear to be single REM generators in the rodent brain and may initiate and orchestrate all REM sleep events, including cortical and hippocampal activation and muscle atonia through distinct pathways. However, severalcell groups in the brainstem and hypothalamus may influence SLDGlut neuron activity, thereby modulating REM sleep timing, amounts, and architecture. Damage to SLDGlut neurons or their projections involved in muscle atonia leads to REM behavior disorder, whereas the abnormal activation of this pathway during wakefulness may underlie cataplexy in narcolepsy. Despite some opposing views, it has become evident that SLDGlut neurons are the sole generators of REM sleep and its associated characteristics. Further research should prioritize a deeper understanding of their cellular, synaptic, and molecular properties, as well as the mechanisms that trigger their activation during cataplexy and make them susceptible in RBD.

Assessing the Physiologic Endotypes Responsible for REM- and NREM-Based OSA

Patients with OSA can have the majority of their respiratory events in rapid eye movement (REM) sleep or in non-rapid eye movement (NREM) sleep. No previous studies have linked the different physiologic conditions in REM and NREM sleep to the common polysomnographic patterns seen in everyday clinical practice, namely REM predominant OSA (REMOSA) and NREM predominant OSA (NREMOSA). (1) How does OSA physiologic condition change with sleep stage in patients with NREMOSA and REMOSA? (2) Do patients with NREMOSA and REMOSA have different underlying OSA pathophysiologic conditions? We recruited patients with three polysomnographic patterns. (1) REMOSA: twice as many respiratory events in REM sleep, (2) NREMOSA: twice as many events in NREM sleep, and (3) uniform OSA: equal number of events in NREM/REM sleep. We deployed a noninvasive phenotyping method to determine OSA endotype traits (Vpassive, Vactive, loop gain, arousal threshold) in NREM sleep, REM sleep, and total night sleep in each group of patients (NREMOSA, REMOSA, uniform OSA). Patients with NREMOSA have significantly worse ventilatory control stability in NREM sleep compared with REM sleep (loop gain, 0.546 [0.456,0.717] in NREM vs0.365 [0.238,0.459] in REM sleep; P= .0026). Patients with REMOSA displayed a significantly more collapsible airway (ie, lower Vpassive) in REM compared with NREM sleep (98.4 [97.3,99.2] %Veupnea in NREM vs95.9 [86.4,98.9] %Veupnea in REM sleep; P< .0001). The major between-group difference across the whole night was a significantly higher loop gain in the NREMOSA group (0.561 [0.429,0.675]) compared with the REMOSA group (0.459 [0.388,0.539]; P= .0033). This study is the first to link long-recognized polysomnographic patterns of OSA to underlying physiologic differences. Patients with NREMOSA have a higher loop gain in NREM sleep; patients with REMOSA have a worsening of Vpassive in REM sleep.

Behavioral manifestations during REM sleep in idiopathic REM sleep behavior disorder

Introduction: Abnormal motor activity in rapid eye movement (REM) sleep is a major video-polysomnographic feature of idiopathic REM sleep behavior disorder (iRBD), which is considered as prodromal stage of synucleinopathies. The diagnosis is based on complex movements visible at the video recording during video-PSG, but more discreet motor manifestations can be observed as well. The aim was to perform a systematic video analysis of motor events in REM sleep.

A circuit perspective on narcolepsy.

The sleep disorder narcolepsy is associated with symptoms related to either boundary state control that include excessive daytime sleepiness and sleep fragmentation, or rapid eye movement (REM) sleep features including cataplexy, sleep paralysis, hallucinations, and sleep-onset REM sleep events (SOREMs). Although the loss of Hypocretin/Orexin (Hcrt/Ox) peptides or their receptors have been associated with the disease, here we propose a circuit perspective of the pathophysiological mechanisms of these narcolepsy symptoms that encompasses brain regions, neuronal circuits, cell types, and transmitters beyond the Hcrt/Ox system. We further discuss future experimental strategies to investigate brain-wide mechanisms of narcolepsy that will be essential for a better understanding and treatment of the disease.

Systemic Injections of Primidone Cause Wake-Inducing Effects in Rats

Background:Essential Tremor (ET) is a disease present in neurodegenerative disorders, such as Parkinson´s disease. Besides the motor dysfunction, ET also causes sleep problems, including excessive daytime sleepiness. To manage ET, several compounds are prescripted, such as primidone. However, no evidence is available regarding the effects of primidone on sleep. &lt;/P&gt;&lt;P&gt; Objective: We analyzed the effects of systemic injections of primidone on sleep in rats. &lt;/P&gt;&lt;P&gt; Method: Rats with sleep electrodes received different doses of primidone (0, 5, 10 or 50mg/Kg, i.p.) at the beginning of the lights-on period. Next, the effects of primidone on the states of vigilance were characterized.Results:At the highest dose of primidone (50mg/Kg), animals displayed an increase in Wakefulness (W) whereas Slow Wave Sleep (SWS) and Rapid Eye Movement Sleep (REMS) were decreased. In addition, sleep parameters such as the number of bouts, mean duration and latency were affected in primidone-treated animals. In this regard, the drug caused an enhancement in the number of bouts of W and SWS while the number of events of REMS showed a diminution. Regarding the mean duration, we found that SWS was decreased after primidone treatments whereas W and REMS remained with no statistical changes. Lastly, the latency of SWS was enhanced in primidone-treated animals while no statistical changes were found in REMS.Conclusion:Our findings demonstrate that primidone, a drug that is used to control ET, provokes wake-inducing effects in rats.

Obstructive events in children with Prader–Willi syndrome occur predominantly during rapid eye movement sleep

ObjectiveChildren with Prader–Willi syndrome (PWS) have a high prevalence of obstructive sleep apnea syndrome (OSAS). In most typically developing children with OSAS, more obstructive apneas and hypopneas occur during rapid eye movement (REM) than during non-REM (NREM) sleep. It was hypothesized that patients with PWS are even more prone to obstructive events in REM sleep than otherwise healthy subjects with OSAS. MethodsPolysomnographic data of patients with PWS and of typically developing children (controls) with OSAS (apnea–hypopnea index [AHI] > 1 episode/h) were analyzed. The two groups were compared regarding obstructive AHI (OAHI), OAHI during NREM sleep (OAHInrem), OAHI during REM sleep (OAHIrem), and the OAHIrem/OAHI ratio (outcome measures). The association between PWS diagnosis and OAHIrem/OAHI was adjusted for confounders using a general linear model. ResultsTwelve children with PWS (median age 7.1 years [interquartile range 3.5, 12.4 years]) and 53 controls (6.5 years [3.9, 8.7 years]) were studied. Children with PWS and controls were similar regarding OAHI (p = 0.21) and OAHInrem (p = 0.76). However, subjects with PWS had higher OAHIrem (17.6 episodes/h [5.8, 25.8 episodes/h]) and OAHIrem/OAHI (2.3 [1.5, 3.2]) than controls (5 episodes/h [1.5, 8.1 episodes/h]; p = 0.002 and 1 [0.5, 2]; p = 0.003, respectively). The association between PWS diagnosis and higher OAHIrem/OAHI persisted after adjustment for age, gender, and obesity (p = 0.009). ConclusionIn children with PWS, OAHI calculated for total sleep time does not reflect OSAS severity during REM sleep, which on average can be twice as high. Mild OSAS in patients with PWS demonstrated by polygraphy without sleep staging may correspond to a moderately-to-severely increased OAHIrem.

Unihemispheric sleep and asymmetrical sleep: behavioral, neurophysiological, and functional perspectives.

Sleep is a behavior characterized by a typical body posture, both eyes’ closure, raised sensory threshold, distinctive electrographic signs, and a marked decrease of motor activity. In addition, sleep is a periodically necessary behavior and therefore, in the majority of animals, it involves the whole brain and body. However, certain marine mammals and species of birds show a different sleep behavior, in which one cerebral hemisphere sleeps while the other is awake. In dolphins, eared seals, and manatees, unihemispheric sleep allows them to have the benefits of sleep, breathing, thermoregulation, and vigilance. In birds, antipredation vigilance is the main function of unihemispheric sleep, but in domestic chicks, it is also associated with brain lateralization or dominance in the control of behavior. Compared to bihemispheric sleep, unihemispheric sleep would mean a reduction of the time spent sleeping and of the associated recovery processes. However, the behavior and health of aquatic mammals and birds does not seem at all impaired by the reduction of sleep. The neural mechanisms of unihemispheric sleep are unknown, but assuming that the neural structures involved in sleep in cetaceans, seals, and birds are similar to those of terrestrial mammals, it is suggested that they involve the interaction of structures of the hypothalamus, basal forebrain, and brain stem. The neural mechanisms promoting wakefulness dominate one side of the brain, while those promoting sleep predominates the other side. For cetaceans, unihemispheric sleep is the only way to sleep, while in seals and birds, unihemispheric sleep events are intermingled with bihemispheric and rapid eye movement sleep events. Electroencephalogram hemispheric asymmetries are also reported during bihemispheric sleep, at awakening, and at sleep onset, as well as being associated with a use-dependent process (local sleep).

The diagnostic value of power spectra analysis of the sleep electroencephalography in narcoleptic patients

ObjectiveManifestations of narcolepsy with cataplexy (NC) include disturbed nocturnal sleep – hereunder sleep–wake instability, decreased latency to rapid eye movement (REM) sleep, and dissociated REM sleep events. In this study, we characterized the electroencephalography (EEG) of various sleep stages in NC versus controls. MethodsEEG power spectral density (PSD) was computed in 136 NC patients and 510 sex- and age-matched controls. Features reflecting differences in PSD curves were computed. A Lasso-regularized regression model was used to find an optimal feature subset, which was validated on 19 NC patients and 708 non-NC patients from a sleep clinic. Reproducible features were analyzed using receiver operating characteristic (ROC) curves. ResultsThirteen features were selected based on the training dataset. Three were applicable in the validation dataset, indicating that NC patients show (1) increased alpha power in REM sleep, (2) decreased sigma power in wakefulness, and (3) decreased delta power in stage N1 versus wakefulness. Sensitivity of these features ranged from 4% to 10% with specificity around 98%, and it did not vary substantially with and without treatment. ConclusionsEEG spectral analysis of REM sleep, wake, and differences between N1 and wakefulness contain diagnostic features of NC. These traits may represent sleepiness and dissociated REM sleep in patients with NC. However, the features are not sufficient for differentiating NC from controls, and further analysis is needed to completely evaluate the diagnostic potential of these features.

The Maintenance of Wakefulness Test in Pediatric Narcolepsy

Objective tools are needed to assess the response to treatment in pediatric narcolepsy. This article presents a single-center experience documenting the use of the maintenance of wakefulness test (MWT) in a pediatric series. This study reviewed the charts of children with narcolepsy who had an MWT performed between January 2008 and June 2012. A cutoff was used for mean sleep latency: <8 minutes for inadequate control of hypersomnia, and >20minutes to indicate adequate control on medications. Thirteen tests were performed on 10 children (median age 15.8 years, range 8.7-20.3 years) with narcolepsy, of which six had cataplexy and three were boys. Comorbid conditions included Prader-Willi syndrome, bipolar affective disorder, and epilepsy (n= 1 each). The median mean sleep latency for all studies was 16 minutes (range 5.8-40 minutes). Sleep-onset rapid eye movement sleep events were seen in three of 13 studies. In seven patients, findings from the MWT resulted in changes in management. These data suggest that the MWT may be a useful and feasible test for assessing response to treatment in children with narcolepsy. Future research is needed to obtain normative MWT data on children with and without narcolepsy.

Chronic agomelatine treatment corrects the abnormalities in the circadian rhythm of motor activity and sleep/wake cycle induced by prenatal restraint stress in adult rats

Agomelatine is a novel antidepressant acting as an MT1/MT2 melatonin receptor agonist/5-HT2C serotonin receptor antagonist. Because of its peculiar pharmacological profile, this drug caters the potential to correct the abnormalities of circadian rhythms associated with mood disorders, including abnormalities of the sleep/wake cycle. Here, we examined the effect of chronic agomelatine treatment on sleep architecture and circadian rhythms of motor activity using the rat model of prenatal restraint stress (PRS) as a putative 'aetiological' model of depression. PRS was delivered to the mothers during the last 10 d of pregnancy. The adult progeny ('PRS rats') showed a reduced duration of slow wave sleep, an increased duration of rapid eye movement (REM) sleep, an increased number of REM sleep events and an increase in motor activity before the beginning of the dark phase of the light/dark cycle. In addition, adult PRS rats showed an increased expression of the transcript of the primary response gene, c-Fos, in the hippocampus just prior to the beginning of the dark phase. All these changes were reversed by a chronic oral treatment with agomelatine (2000 ppm in the diet). The effect of agomelatine on sleep was largely attenuated by treatment with the MT1/MT2 melatonin receptor antagonist, S22153, which caused PRS-like sleep disturbances on its own. These data provide the first evidence that agomelatine corrects sleep architecture and restores circadian homeostasis in a preclinical model of depression and supports the value of agomelatine as a novel antidepressant that resynchronizes circadian rhythms under pathological conditions.

Interictal epileptiform discharges and phasic phenomena of REM sleep

The objective of this study was to assess the effect of phasic rapid eye movement (REM) sleep events on interictal epileptiform discharges (IEDs). Twelve patients with focal epilepsy and IEDs during REM sleep were examined by video-EEG monitoring. The number of IEDs was calculated in different REM sleep episodes according to the rate of rapid eye movements. A negative correlation was identified between the occurrence of rapid eye movements and IEDs, indicating that the suppression of propagation of IEDs during REM sleep is enhanced by phasic REM sleep events, probably as a result of phasic activation of cholinergic neurons of the ponto-mesencephalic tegmentum. This study demonstrates that the degree of EEG desynchronization and IEDs is influenced by REM density.

Atrioventricular Block During the Phasic Events of REM Sleep in a Patient with Severe Obstructive Sleep Apnea Syndrome

Patients with obstructive sleep apnea syndrome (OSAS) sometimes have atrioventricular (AV) block during sleep. However, significant resolution of such AV block with treatment for OSAS has been reported. On the other hand, during rapid eye movement (REM) sleep, conduction disturbances not associated with the apnea event can be observed, particularly in young healthy subjects. We report the case of a 67-year-old man with severe OSAS and 2:1 AV block that occurred only during the phasic events of REM sleep; continuous positive airway pressure (CPAP) treatment did not result in resolution of the AV block. No specific abnormalities were found on cardiac evaluation. Based on the analysis of overnight heart rate variability, CPAP treatment resulted in a markedly reduced ratio of low-frequency to high-frequency power and an increased high-frequency power, though high-frequency power was not increased during REM sleep on CPAP.

The role of vestibular system and the cerebellum in adapting to gravitoinertial, spatial orientation and postural challenges of REM sleep

The underlying reasons for, and mechanisms of rapid eye movement (REM) sleep events remain a mystery. The mystery has arisen from interpreting REM sleep events as occurring in 'isolation' from the world at large, and phylogenetically ancient brain areas using 'primal' gravity-dependent coordinates, reflexes and stimuli parameters to relay and process information about self and environment. This paper views REM sleep as a phylogenetically older form of wakefulness, wherein the brain uses a gravitoinertial-centred reference frame and an internal self-object model to evaluate and integrate inputs from several sensory systems and to adapt to spatial-temporal disintegration and malignant cholinergic-induced vasodepressor/ventilatory threat. The integration of vestibular and non-vestibular sensory graviceptor signals enables estimation and control of centre of the body mass, position and spatial relationship of body parts, gaze, head and whole-body tilt, spatial orientation and autonomic functions relative to gravity. The vestibulocerebellum and vermis, via vestibular and fastigial nucleus, coordinate inputs and outputs from several sensory systems and modulate the amplitude and duration of 'fight-or-flight' vestibulo-orienting and autonomic 'burst' responses to overcome the ongoing challenges. Resolving multisystem conflicts during the unique stresses (gravitoinertial, hypoxic, thermal, immobilisation, etc.) of REM sleep enables learning, cross-modal plasticity, higher-order integration and multidimensional spatial updating of sensory-motor-cognitive components. This paper aims to generate discussion, reinterpretation and creative testing of this novel hypothesis, which, if experimentally confirmed, has major implications across medicine, bioscience and space physiology, from developmental, clinical, research and theoretical perspectives.

Electrical stimulation of the cholinergic laterodorsal tegmental nucleus elicits scopolamine-sensitive excitatory postsynaptic potentials in medial pontine reticular formation neurons

A large and consistent body of data implicates mesopontine cholinergic neurons in the production of rapid eye movement sleep, and indicates that many rapid eye movement sleep events are mediated by activation of pontine reticular formation neurons. There is anatomical evidence for projections from the mesopontine cholinergic nuclei to the pontine reticular formation, but no study has shown that stimulation of this cholinergic zone produces excitatory postsynaptic potentials in pontine reticular formation neurons. In the present study, intracellular recordings were made from 168 pontine reticular formation neurons, identified by antidromic activation from the bulbar reticular formation and by neurobiotin intracellular labeling, in acutely anesthetized cats. The effects of single-pulse electrical stimulation of the laterordorsal tegmental nucleus portion of the ipsilateral mesopontine cholinergic zone were evaluated in these neurons. Under urethane anesthesia this stimulation produced, in 21 of 22 recorded neurons, long-latency excitatory postsynaptic potentials (mean = 3 ms), consistent with the conduction velocity of unmyelinated cholinergic fibers (measured conduction velocity was 2 m/s). This excitatory postsynaptic potential was virtually abolished by intravenous administration of the muscarinic cholinergic receptor blocker scopolamine ( n = 40 neurons), and by acute cuts separating the laterodorsal tegmental nucleus and the recorded neurons ( n = 40). In contrast, a short-latency excitatory postsynaptic potential (0.7–1.5 ms) was not reduced in amplitude by scopolamine and could still be elicited following acute transverse cuts. Unlike the longer-latency excitatory postsynaptic potential, its amplitude was not reduced by barbiturate anesthesia. These data, suggesting the presence of an excitatory, cholinergic laterodorsal tegmental nucleus projection to the pontine reticular formation, provide further support to other lines of evidence implicating mesopontine cholinergic neurons in the production of rapid eye movement sleep, and are compatible with a model of rapid eye movement sleep generation in which a key element is mesopontine cholinergic input depolarizing and increasing the excitability of reticular core neurons.

Effects of REM Sleep on the Ventilatory Response to Airway Occlusion in the Dog

We determined the effects of sleep state on the ventilatory response following transient airway occlusion and on the response to vagal blockade in the unanesthetized sleeping dog. Three tracheotomized dogs underwent repeated occlusions (159 trials) during rapid eye movement (REM) and nonrapid eye movement (NREM) sleep. In all sleep states we found significant but variable transient hyperventilation following release of occlusion. In NREM sleep, a significant central apnea [expiratory time (TE) prolonged 2-10 times control] followed the hyperpneic response, so long as the increase in tidal volume (VT) during the hyperpnea exceeded three times control VT, that is, a volume-dependent apneic threshold. In REM sleep with maintained levels of eye movement density, hyperventilation commonly followed release of obstruction but only very rarely did VT exceed the volume threshold, and central apnea was rare. Cervical vagal blockade was used to show that significant inhibitory pulmonary stretch receptor reflexes were present in both NREM and REM sleep, although the strength of the reflex was diminished in REM. We postulate that the phasic events of REM sleep inhibit the increase in VT in response to the chemical stimuli accumulated during airway occlusion and also interfere with the prolongation of TE in response to lung stretch and/or transient hypocapnia. The result is that central apnea occurs only very rarely in REM sleep.

Effects of Continuous Positive Airway Pressure on Phasic Events of REM Sleep in Patients with Obstructive Sleep Apnea

In patients with obstructive sleep apnea and associated rapid-eye-movement (REM) sleep deprivation and disruption, the first night of nasal continuous positive airway pressure (CPAP) is often associated with increases in REM sleep time and REM density (REM rebound). The amount of REM rebound, however, varies considerably. We sought to characterize the magnitude of REM rebound and to determine what factors determine individual differences in REM rebound with initial CPAP treatment. Twenty-six patients with sleep apnea had a baseline nocturnal polysomnogram and a second night with a trial of CPAP. REM sleep time increased by 69% with CPAP, REM density increased by 73%, and REM activity by 169%. REM density was highest in the second REM period. Improvement in respiratory disturbance index with CPAP correlated significantly with increased minutes of REM sleep with CPAP. Of polysomnographic measures on the baseline night, change in minutes of REM sleep with CPAP correlated best with minimum oxygen saturation and to a lesser degree with respiratory disturbance index, and minutes of Stage 1 sleep. One possible explanation for the effect of hypoxemia on subsequent REM rebound is that some physiological functions of REM sleep may fail when oxygen saturation falls below a certain level.

Brain stem gigantocellular neurons: patterns of activity during behavior and sleep in the freely moving rat

1. The activity of 44 single brain stem gigantocellular neurons was recorded in the freely moving rat during the following four states: quiet waking (W), waking with movement (W-M), slow-wave sleep (SWS), and rapid eye movement (REM) sleep. 2. Cells were classified into three groups on the basis of the states in which they maintained their highest rate of discharge. The three cell categories were: movement-REM (MOV-REM), movement (MOV), and quiet waking (QW) neurons. The MOV-REM neurons, comprising 68% of the cell population, discharged significantly more during waking-movement and REM sleep than during either W or SWS. The MOV neurons, 16% of the cells, showed significant increases in activity only when the rat moved. The QW neurons, also 16% of the cells, typically maintained high rates of discharge in the absence of movement. 3. The MOV-REM neurons were further divided into two subclasses of cells--phasically and tonically discharging neurons. The phasic MOV-REM cells appeared to participate in phasic motor events of REM sleep and corresponding movements during waking. The pattern of activity of the tonic MOV-REM neurons suggested that they may be involved in the generation and maintenance of the theta rhythm of the hippocampus during waking-movement and REM sleep. 4. No cells were found to discharge significantly more in REM sleep or SWS sleep than in the other states, (i.e., no REM or SWS selective cells were seen).

Neuronal activity specific to REM sleep and its relationship to breathing

The search for the neural substrate of a state of consciousness has led to the expectation that there may be neurons which discharge tonically and rhythmically during that state alone. We have now recorded in the cat the first evidence of neurons whose rhythmic discharge is consistent with the hypothesis of a tonically active neural substrate for rapid eye movement (REM) sleep. These neurons, located in the area of gigantocellular and lateral medullary tegmental fields, begin rhythmically discharging simultaneously with the cortical desynchronization at REM sleep onset and cease firing at arousal from REM; they are essentially silent at all other times. Modulations of the discharge rate correlate with the phasic events of REM sleep, such as ataxic breathing and eye movement bursts. In addition, there is a high correlation between their discharge rate and respiratory frequency analyzed on a breath-by-breath basis. The significant rhythmicity of their discharge coupled with high REM selectivity contrasts them with putative REM generators reported by others in the pons and suggests their crucial role in REM generation.

The role of serotonin and norepinephrine in sleep-waking activity.

A critical review of the evidences relating the biogenic amines serotonin and norepinephrine to the states of slow-wave and rapid eye movement (REM) sleep is presented. Various alternative explanations for specific chemical regulation of the individual sleep states, including the phasic events of REM sleep, are evaluated within the overall framework of the monoamine theory of sleep. Several critical neuropsychopharmacological studies relating to metabolsim of the amines in relation to sleep-waking behavior are presented. Models of the chemical neuronal circuitry involved in sleep-waking activity are derived and interactions between several brainstem nuclei, particularly the raphé complex and locus coeruleus, are discussed. Activity in these aminergic systems in relation to oscillations in the sleep-waking cycles is evaluated. In particular, the assessment of single cell activity in specific chemical systems in relations to chemical models of sleep is reviewed. Overall, it appears that the biogenic amines, especially serotonin and norepinephrine, play key roles in the generation and maintenance of the sleep states. These neurotransmitters participate in some manner in the "triggering" processes necessary for actuating each sleep phase and in regulating the transitions from sleep to waking activity. The biogenic amines are, however, probably not "sleep factors" or direct inducers of the sleep states. Rather, they appear to be components of a multiplicity of interacting chemical circuitry in the brain whose activity maintains various chemical balances in different brain regions. Shifts in these balances appear to be involved in the triggering and maintenance of the various states comprising the vigilance continuum.