Physiological and anatomical link between Parkinson-like disease and REM sleep behavior disorder

Parkinson's disease (PD) is a progressive neurodegenerative disease that is caused by a loss of neurons in the ventral midbrain. Parkinsonian patients often experience insomnia, parasomnias, and daytime somnolence. REM sleep behavior disorder (RBD) is characterized by vigorous movements during REM sleep, and may also be caused by neuronal degeneration in the central nervous system (CNS); however, the site of degeneration remains unclear. Both Parkinsonism and RBD become more prevalent with aging, with onset usually occurring in the sixties. Recent findings show that many individuals with RBD eventually develop Parkinsonism. Conversely, it is also true that certain patients diagnosed with Parkinsonism subsequently develop RBD. Postmortem examination reveals that Lewy bodies, Lewy neurites, and alpha-synuclein are found in brainstem nuclei in both Parkinsonism and RBD patients. In this article, we will discuss evidence that Parkinsonism and RBD are physiologically and anatomically linked, based on our animal experiments and other studies on human patients.     

Control of motoneuron function and muscle tone during REM sleep, REM sleep behavior disorder and cataplexy/narcolepsy

REM sleep triggers a potent suppression of postural muscle tone - i.e., REM atonia. However, motor control during REM sleep is paradoxical because overall brain activity is maximal, but motor output is minimal. The skeletal motor system remains quiescent during REM sleep because somatic motoneurons are powerfully inactivated. Determining the mechanisms triggering loss of motoneuron function during REM sleep is important because breakdown in REM sleep motor control underlies sleep disorders such as REM sleep behavior disorder (RBD) and cataplexy/narcolepsy. For example, RBD is characterized by dramatic REM motor activation resulting in dream enactment and subsequent patient injury. In contrast, cataplexy a pathognomonic symptom of narcolepsy - is caused by the involuntary onset of REM-like atonia during wakefulness. This review highlights recent work from my laboratory that examines how motoneuron function is lost during normal REM sleep and it also identifies potential biochemical mechanisms underlying abnormal motor control in both RBD and cataplexy. First, I show that both GABAB and GABAA/glycine mediated inhibition of motoneurons is required for generating REM atonia. Next, I show that impaired GABA and glycine neurotransmission triggers the cardinal features of RBD in a transgenic mouse model. Last, I show that loss of an excitatory noradrenergic drive onto motoneurons is, at least in part, responsible for the loss of postural muscle tone during cataplexy in narcoleptic mice. Together, this research indicates that multiple transmitters systems are responsible for regulating postural muscle tone during REM sleep, RBD and cataplexy.     

Sleep-Related Declarative Memory Consolidation and Verbal Replay during Sleep Talking in Patients with REM Sleep Behavior Disorder

Objective

To determine if sleep talkers with REM sleep behavior disorder (RBD) would utter during REM sleep sentences learned before sleep, and to evaluate their verbal memory consolidation during sleep.

Methods

Eighteen patients with RBD and 10 controls performed two verbal memory tasks (16 words from the Free and Cued Selective Reminding Test and a 220-263 word long modified Story Recall Test) in the evening, followed by nocturnal video-polysomnography and morning recall (night-time consolidation). In 9 patients with RBD, daytime consolidation (morning learning/recall, evening recall) was also evaluated with the modified Story Recall Test in a cross-over order. Two RBD patients with dementia were studied separately. Sleep talking was recorded using video-polysomnography, and the utterances were compared to the studied texts by two external judges.

Results

Sleep-related verbal memory consolidation was maintained in patients with RBD (+24±36% words) as in controls (+9±18%, p=0.3). The two demented patients with RBD also exhibited excellent nighttime consolidation. The post-sleep performance was unrelated to the sleep measures (including continuity, stages, fragmentation and apnea-hypopnea index). Daytime consolidation (-9±19%) was worse than night-time consolidation (+29±45%, p=0.03) in the subgroup of 9 patients with RBD. Eleven patients with RBD spoke during REM sleep and pronounced a median of 20 words, which represented 0.0003% of sleep with spoken language. A single patient uttered a sentence that was judged to be semantically (but not literally) related to the text learned before sleep.

Conclusion

Verbal declarative memory normally consolidates during sleep in patients with RBD. The incorporation of learned material within REM sleep-associated sleep talking in one patient (unbeknownst to himself) at the semantic level suggests a replay at a highly cognitive creative level.     

Evidence for the re-enactment of a recently learned behavior during sleepwalking

Animal studies have shown that sequenced patterns of neuronal activity may be replayed during sleep. However, the existence of such replay in humans has not yet been directly demonstrated. Here we studied patients who exhibit overt behaviors during sleep to test whether sequences of movements trained during the day may be spontaneously reenacted by the patients during sleep. We recruited 19 sleepwalkers (who displayed complex and purposeful behaviors emerging from non REM sleep), 20 patients with REM sleep behavior disorder (who enacted their dreams in REM sleep) and 18 healthy controls. Continuous video sleep recordings were performed during sleep following intensive training on a sequence of large movements (learned during a variant of the serial reaction time task). Both patient groups showed learning of the intensively trained motor sequence after sleep. We report the re-enactment of a fragment of the recently trained motor behavior during one sleepwalking episode. This study provides, to our knowledge, the first evidence of a temporally-structured replay of a learned behavior during sleep in humans. Our observation also suggests that the study of such sleep disorders may provide unique and critical information about cognitive functions operating during sleep.     

Dream imagery,rapid eye movement sleep behavior disorder,and hallucinations

Rapid eye movement (REM) sleep behavior disorder (RBD) and hypnagogic hallucinations are salient symptoms of abnormal and dissociated REM sleep that are frequently associated in serious neurological diseases. RBD is a strong, independent risk factor for hallucinations in narcolepsy (odds ratio: 4.3) and in Parkinson’s disease (odds ratio: 2.7). In Parkinson’s disease, RBD also predicts incident hallucinations and psychosis in prospective cohorts. Status dissociatus (a mixture of hallucinations, RBD, and dissociated sleep-wake states) is observed in patients with Guillain-Barré when hallucinating, but also in Lewy bodies dementia, delirium tremens, fatal familial insomnia, and Morvan’s chorea. This co-occurrence of RBD and visual hallucinations suggests a common, extensive lesion within REM sleep executive systems.

     

Brainstem structures involved in rapid eye movement sleep behavior disorder

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during paradoxical (REM) sleep (PS). The neuronal dysfunctions responsible for RBD are not known. In the present review, we propose an updated integrated model of the mechanisms responsible for PS and explore different hypotheses explaining RBD. We propose that RBD appears based on a specific degeneration of PS-on glutamatergic neurons localized in the caudal pontine sublaterodorsal tegmental nucleus or the glycinergic/GABAergic premotoneurons localized in the medullary ventral gigantocellular reticular nucleus.

     

Spectrum of rapid eye movement sleep behavior disorder (overlap between rapid eye movement sleep behavior disorder and other parasomnias)

Parasomnia Overlap Disorder (POD) was described and named in 1997 with a series of 33 cases of rapid eye movement (REM) sleep behavior disorder (RBD) combined with a disorder of arousal from non-rapid eye movement (NREM) sleep (sleepwalking, sleep terrors) that emerged idiopathically or symptomatically with neurological and other disorders. POD is a subtype of RBD in the International Classification of Sleep Disorders Diagnostic and Coding Manual, second edition (ICSD-2). An updated classification of POD also includes subclinical RBD-NREM parasomnia, RBD-sleep-related eating disorder, RBD-sexsomnia, RBD-rhythmic movement disorder, and status dissociatus (SD), which is another subtype of RBD in the ICSD-2. Similar to POD, a core feature of SD is sleep motor-behavioral dyscontrol, with release of dream-related behaviors suggestive of RBD, but with nearly continuous ambiguous polygraphic sleep precluding the identification of NREM/REM sleep states. SD exemplifies extreme state dissociation. SD is always a symptomatic disorder, and is causally associated with a broad range of neurologic disorders, often with thalamic, limbic, striatal, and pontine involvement. The parasomnia behaviors associated with POD and SD — typical RBD behaviors — can often be controlled with bedtime clonazepam therapy, including the abnormal dreaming.

     

Brainstem and spinal cord circuitry regulating REM sleep and muscle atonia

Background

Previous work has suggested, but not demonstrated directly, a critical role for both glutamatergic and GABAergic neurons of the pontine tegmentum in the regulation of rapid eye movement (REM) sleep.

Methodology/Principal Findings

To determine the in vivo roles of these fast-acting neurotransmitters in putative REM pontine circuits, we injected an adeno-associated viral vector expressing Cre recombinase (AAV-Cre) into mice harboring lox-P modified alleles of either the vesicular glutamate transporter 2 (VGLUT2) or vesicular GABA-glycine transporter (VGAT) genes. Our results show that glutamatergic neurons of the sublaterodorsal nucleus (SLD) and glycinergic/GABAergic interneurons of the spinal ventral horn contribute to REM atonia, whereas a separate population of glutamatergic neurons in the caudal laterodorsal tegmental nucleus (cLDT) and SLD are important for REM sleep generation. Our results further suggest that presynaptic GABA release in the cLDT-SLD, ventrolateral periaqueductal gray matter (vlPAG) and lateral pontine tegmentum (LPT) are not critically involved in REM sleep control.

Conclusions/Significance

These findings reveal the critical and divergent in vivo role of pontine glutamate and spinal cord GABA/glycine in the regulation of REM sleep and atonia and suggest a possible etiological basis for REM sleep behavior disorder (RBD).     

The 'scanning hypothesis' of rapid eye movements during REM sleep: a review of the evidence

Rapid eye movements (REMs) and visual dreams are salient features of REM sleep. However, it is unclear whether the eyes scan dream images. Several lines of evidence oppose the scanning hypothesis: REMs persist in animals and humans without sight (pontine cats, foetus, neonates, born-blinds), some binocular REMs are not conjugated (no focus point), REMs occur in parallel (not in series) with the stimulation of the visual cortex by ponto-geniculo-occipital spikes, and visual dreams can be obtained in non REM sleep. Studies that retrospectively compared the direction of REMs to dream recall recorded after having awakened the sleeper yielded inconsistent results, with a concordance varying from 9 to 80%. However, this method was subject to methodological flaws, including the bias of retrospection and neck atonia that does not allow the determination of the exact direction of gaze. Using the model of RBD (in which patients are able to enact their dreams due to the absence of muscle atonia) in 56 patients, we directly determined if the eyes moved in the same directions as the head and limbs. When REMs accompanied goal-oriented motor behaviour during RBD (e.g., framing something, greeting with the hand, climbing a ladder), 90% were directed towards the action of the patient (same plane and direction). REMs were however absent in 38% of goal-oriented behaviours. This directional coherence between limbs, head and eye movements during RBD suggests that, when present, REMs imitate the scanning of the dream scene. Because REMs index and complexity were similar in patients with RBD and controls, this concordance can be extended to normal REM sleep. These results are consistent with the model of a brainstem generator activating simultaneously images, sounds, limbs movements and REMs in a coordinated parallel manner, as in a virtual reality.     

Phenomenology of rapid eye movement (REM) sleep behavior disorder in Parkinson’s disease: A descriptive study using the REM sleep behavior disorder severity scale (RBDSS)

Using the rapid eye movement (REM) sleep behavior disorder severity scale (RBDSS) as a reliable clinical tool we further assessed the phenomenology of REM sleep behavior disorder (RBD) in 56 Parkinson’s disease patients with RBD. The scale uses phenomenological categories based on the localization of movements in the distal or proximal extremities and/or involving the trunc and on the presence or absence of vocalizations. Interrater reliability has been published previously. In the current study we looked into the distribution of motor and vocal phenomena. We identified a small percentage of patients with only vocalizations (4/56), and 8/56 patients with and 10/56 patients without vocalizations and small nonviolent movements of the distal extremities or facial jerks. Ten patients showed more forceful movements of the proximal extremities, 11 patients with movements involving the proximal extremities had additional vocalizations, 5 patients were recorded with axial involvement, and 12 patients with axial movements and vocalizations. These findings underline the clinical variety of RBD manifestation in Parkinson’s disease patients without a certain pattern. However, both extreme variants, the mild one and the violent one, are rare. The RBDSS facilitates the risk estimate for harmful behaviors and may be recommended for comparative studies on RBD and its pharmacotherapy.

     

Sleep disorders in elderly, the sleep apnea syndrome in particular: are they a cause of insomnia? A review of literature

In this publication a review is presented based on the findings resulting from sleep-wake investigations searching for sleep disorders associated with insomnia in relatively healthy elderly. 44 Relevant journal articles published between 1980-1998 were found. The four most important sleep disorders which can be accompanied by sleeplessness in relatively healthy elderly people are periodic leg movements disorder (PLM), restless legs syndrome (RLS), REM sleep behaviour disorder (RBD) and sleep apnea syndrome (SAS). Of these disorders, sleep apnea and periodic leg movements occur most frequently, in a quarter of the elderly. The latter, however, seldom complain about sleeplessness. Within the category of older people disorders characterized by movements during sleep increase significantly with age, nightly respiration disorders do not. SAS, PLM and RBD appear most frequently in men and RLS in women. The disorders characterized by movements during sleep (especially RLS and RBD) are often accompanied by sleeplessness. SAS, however, is more closely associated with day-time sleepiness than with sleeplessness. No combination of demographic variables and symptoms allows a reliable prediction of these sleep disorders. Fortunately, these disorders are not a major threat to the health of older people.     

快速眼动睡眠期行为障碍(RBD)的帕金森病临床特征分析

目的:探究合并不同发作形式的快速眼动睡眠期行为障碍(RBD)与帕金森病的临床特点及自主神经功能障碍变化。方法:采用快速眼动期睡眠行为障碍筛查量表及帕金森综合评分量表(Unified Parkinson's disease rating scale),对20例合并简单型(RBD)的帕金森病患者(RBD-简单组)与20例合并复杂型(RBD)的帕金森病患者(RBD-复杂组)进行研究。结果:两组帕金森病患者的一般情况、左旋多巴药物日剂量、疾病病程等无统计学差异(P>0.05)。合并复杂型(RBD)的帕金森病患者运动部分评分高于合并简单型(RBD)的帕金森病患者(P<0.05)。两组患者之间在非震颤、强直、运动减少症状均存在统计学差异(P<0.05),(RBD)复杂组评分均高于(RBD)简单组。多因素logistics回归显示,复杂型(RBD)的存在与UPDRS-Ш部分评分相关,而与年龄、病程、教育年限、左旋多巴药物日剂量等无显著相关,与运动减少症状最为相关,与震颤、非震颤、强直症状无相关性。两组患者运动障碍类型与(RBD)发作形式无明显相关性(P=0.108)。结论:合并复杂型(RBD)的帕金森病患者运动症状更重,并且累及运动障碍的诸多方面。帕金森病患者存在复杂型(RBD)症状主要与UPDRS-Ш评分相关,其中与运动减少方面显著相关。     

Spontaneous hemodynamic oscillations during human sleep and sleep stage transitions characterized with near-infrared spectroscopy

Understanding the interaction between the nervous system and cerebral vasculature is fundamental to forming a complete picture of the neurophysiology of sleep and its role in maintaining physiological homeostasis. However, the intrinsic hemodynamics of slow-wave sleep (SWS) are still poorly known. We carried out 30 all-night sleep measurements with combined near-infrared spectroscopy (NIRS) and polysomnography to investigate spontaneous hemodynamic behavior in SWS compared to light (LS) and rapid-eye-movement sleep (REM). In particular, we concentrated on slow oscillations (3-150 mHz) in oxy- and deoxyhemoglobin concentrations, heart rate, arterial oxygen saturation, and the pulsation amplitude of the photoplethysmographic signal. We also analyzed the behavior of these variables during sleep stage transitions. The results indicate that slow spontaneous cortical and systemic hemodynamic activity is reduced in SWS compared to LS, REM, and wakefulness. This behavior may be explained by neuronal synchronization observed in electrophysiological studies of SWS and a reduction in autonomic nervous system activity. Also, sleep stage transitions are asymmetric, so that the SWS-to-LS and LS-to-REM transitions, which are associated with an increase in the complexity of cortical electrophysiological activity, are characterized by more dramatic hemodynamic changes than the opposite transitions. Thus, it appears that while the onset of SWS and termination of REM occur only as gradual processes over time, the termination of SWS and onset of REM may be triggered more abruptly by a particular physiological event or condition. The results suggest that scalp hemodynamic changes should be considered alongside cortical hemodynamic changes in NIRS sleep studies to assess the interaction between the autonomic and central nervous systems.     

Temporally structured replay of awake hippocampal ensemble activity during rapid eye movement sleep

Human dreaming occurs during rapid eye movement (REM) sleep. To investigate the structure of neural activity during REM sleep, we simultaneously recorded the activity of multiple neurons in the rat hippocampus during both sleep and awake behavior. We show that temporally sequenced ensemble firing rate patterns reflecting tens of seconds to minutes of behavioral experience are reproduced during REM episodes at an equivalent timescale. Furthermore, within such REM episodes behavior-dependent modulation of the subcortically driven theta rhythm is also reproduced. These results demonstrate that long temporal sequences of patterned multineuronal activity suggestive of episodic memory traces are reactivated during REM sleep. Such reactivation may be important for memory processing and provides a basis for the electrophysiological examination of the content of dream states.     

Cognitive dysfunction in rapid eye movement sleep behavior disorder

Cognitive impairment is a frequent feature of rapid eye movement sleep behavior disorder (RBD). The cognitive profile of RBD patients is heterogeneous, with impairments in attention, executive functions, episodic memory, and visuospatial abilities. Moreover, over 50% of RBD patients meet the diagnostic criteria for mild cognitive impairment (MCI). Although a comprehensive neuropsychological assessment remains the most sensitive way to detect MCI, three cognitive screening tests have been validated in RBD. The Montreal Cognitive Assessment was found to be the most appropriate screening test for detecting MCI in RBD. In addition RBD in Parkinson’s disease may be a risk factor for MCI and dementia.

     

Predicting neurodegenerative disease in idiopathic rapid eye movement (REM) sleep behavior disorder: Conference proceedings,REM Sleep Behavior Symposium 2011

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment behavior during rapid eye movement sleep, which is generally related to damage of pontomedullary structures. Idiopathic RBD is a well-established risk factor for neurodegenerative disease; at least 40-65% of patients with idiopathic RBD will develop a defined neurodegenerative phenotype over 10 years. This is almost always a “synucleinopathy” (Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy). Often, patients develop a syndrome with overlapping parkinsonism and cognitive impairment. The ability of RBD to predict disease has major implications for development of neuroprotective therapy, by providing a high-risk prodromal group for neuro-protective trials. In addition, it allows testing of other predictive markers of neurodegeneration. Recent prospective studies found that idiopathic RBD patients with abnormal olfaction at baseline had a 65% 5-year risk of developing neurodegenerative disease, compared with a 14% risk in those with normal olfaction. Those with abnormal color vision had a 74% risk of neurodegenerative disease compared with 26% in those with normal vision. Additionally, neuroimaging markers of the sub-stantia nigra including dopaminergic functional imaging and transcranial ultrasound have been able to predict imminent development of defined neurodegenerative disease in RBD, although sensitivity and lead time have not been established. Future studies will continue to expand the list of predictive markers of neurodegeneration and will better define specificity, sensitivity, and lead time of prodromal markers.

     

Occlusion pressure and ventilation during sleep in normal humans

Previous investigation in normal humans has demonstrated reduced ventilation and ventilatory responses to chemical stimuli during sleep. Most have interpreted this to be a product of decreasing central nervous system sensitivity to the normal stimuli that maintain ventilation, whereas other factors such as increasing airflow resistance could also contribute to this reduction in respiration. To improve our understanding of these events, we measured ventilation and occlusion pressures (P0.1) during unstimulated ventilation and rebreathing-induced hypercapnia during wakefulness and non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. Eighteen subjects (10 males and 8 females) of whom seven were snorers (5 males and 2 females) were studied. Ventilation was reduced during both NREM and REM sleep (P less than 0.05), but this decrement in minute ventilation tended to be greater in snorers than nonsnorers. Unstimulated P0.1, on the other hand, was maintained or increased during sleep in all groups studied, with males and snorers showing the largest increase. The hypercapnic ventilatory response fell during both NREM and REM sleep and tended to be lower during REM than NREM sleep. However, the P0.1 response to hypercapnia during NREM sleep was well maintained at the waking level although the REM response was statistically reduced. These studies suggest that the mechanism of the reduction in ventilation and the hypercapnic ventilatory response seen during sleep, particularly NREM sleep, is likely to be multifactorial and not totally a product of decreasing central respiratory drive.     

Promotion of sleep by targeting the orexin system in rats, dogs and humans

Orexins are hypothalamic peptides that play an important role in maintaining wakefulness in mammals. Permanent deficit in orexinergic function is a pathophysiological hallmark of rodent, canine and human narcolepsy. Here we report that in rats, dogs and humans, somnolence is induced by pharmacological blockade of both orexin OX(1) and OX(2) receptors. When administered orally during the active period of the circadian cycle, a dual antagonist increased, in rats, electrophysiological indices of both non-REM and, particularly, REM sleep, in contrast to GABA(A) receptor modulators; in dogs, it caused somnolence and increased surrogate markers of REM sleep; and in humans, it caused subjective and objective electrophysiological signs of sleep. No signs of cataplexy were observed, in contrast to the rodent, dog or human narcolepsy syndromes. These results open new perspectives for investigating the role of endogenous orexins in sleep-wake regulation.     

Short-term complexity of cardiac autonomic control during sleep: REM as a potential risk factor for cardiovascular system in aging

Introduction

Sleep is a complex phenomenon characterized by important modifications throughout life and by changes of autonomic cardiovascular control. Aging is associated with a reduction of the overall heart rate variability (HRV) and a decrease of complexity of autonomic cardiac regulation. The aim of our study was to evaluate the HRV complexity using two entropy-derived measures, Shannon Entropy (SE) and Corrected Conditional Entropy (CCE), during sleep in young and older subjects.

Methods

A polysomnographic study was performed in 12 healthy young (21.1±0.8 years) and 12 healthy older subjects (64.9±1.9 years). After the sleep scoring, heart period time series were divided into wake (W), Stage 1–2 (S1-2), Stage 3–4 (S3-4) and REM. Two complexity indexes were assessed: SE(3) measuring the complexity of a distribution of 3-beat patterns (SE(3) is higher when all the patterns are identically distributed and it is lower when some patterns are more likely) and CCE_min measuring the minimum amount of information that cannot be derived from the knowledge of previous values.

Results

Across the different sleep stages, young subjects had similar RR interval, total variance, SE(3) and CCE_min. In the older group, SE(3) and CCE_min were reduced during REM sleep compared to S1-2, S3-4 and W. Compared to young subjects, during W and sleep the older subjects showed a lower RR interval and reduced total variance as well as a significant reduction of SE(3) and CCE_min. This decrease of entropy measures was more evident during REM sleep.

Conclusion

Our study indicates that aging is characterized by a reduction of entropy indices of cardiovascular variability during wake/sleep cycle, more evident during REM sleep. We conclude that during aging REM sleep is associated with a simplification of cardiac control mechanisms that could lead to an impaired ability of the cardiovascular system to react to cardiovascular adverse events.     

Mechanisms and models of REM sleep control

The first sections of this paper survey the history and recent developments relevant to the major neurotransmitters and neuromodulators involved in REM sleep control. The last portion of this paper proposes a structural model of cellular interaction that produces the REM sleep cycle, and constitutes a further revision of the reciprocal interaction model This paper proposes seven criteria to define a causal role in REM sleep control for putative neuro-transmitters/modulators. The principal criteria are measurements during behavioral state changes of the extracellular concentrations of the putative substances, and electrophysiological recording of their neuronal source. A cautionary note is that, while pharmacological manipulations are suggestive, they alone do not provide definitive causal evidence. The extensive body of in vivo and in vitro evidence supporting cholinergic promotion of REM sleep via LDT/PPT neuronal activity is surveyed. An interesting question raised by some studies is whether cholinergic influences in rat are less puissant than in cat. At least some of the apparent lesser REM-inducing effect of carbachol in the rat may be due to incomplete control of circadian influences; almost all experiments have been run only in the daytime, inactive period, when REM sleep is more prominent, rather than in the REM-sparse nighttime inactive period. Monoaminergic inhibition of cholinergic neurons, once thought to be the most shaky proposal of the reciprocal interaction model, now enjoys considerable support from both in vivo and in vitro data. However, the observed time course of monoaminergic neurons, their "turning off" discharge activity as REM sleep is approached and entered would seem to be difficult to produce from feedback inhibition, as originally postulated by the reciprocal interaction model. New data suggest the possibility that GABAergic inhibition of Locus Coeruleus and Dorsal Raphe monoaminergic neurons may account for the "REM-off" neurons turning off. However, the source(s) of GABAergic influences suggested by anatomical studies has yet to be definitively identified by electrophysiological recordings of GABAergic neurons that show the requisite inverse time course of activity relative to monoaminergic neurons. New and still preliminary microdialysis data suggest that reticular formation neurons, the effector neurons for REM sleep phenomena, might be disinhibited during REM sleep by decreased GABAergic influence, perhaps stemming from REM-on cholinergic neuronal inhibition of reticular formation GABAergic neurons. Whether the postulated cholinergic inhibition of GABAergic neurons is present is testable with in vitro recordings and double labeling. Taking into account the observed data on neuro-modulators/transmitters, a structural model incorporating interaction of REM-on and REM-off neurons and GABAergic influences is proposed. Finally, with respect to orexin and REM sleep, it is hypothesized that orexinergic activity may be a principal factor controlling REM sleep's absence from the active period in strongly circadian animals such as rat and man.