Rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia in narcolepsy

Narcolepsy is a rare disabling hypersomnia disorder that may include cataplexy, sleep paralysis, hypnagogic hallucinations, and sleep-onset rapid eye movement (REM) periods, but also disrupted nighttime sleep by nocturnal awakenings, and REM sleep behavior disorder (RBD). RBD is characterized by dream-enacting behavior and impaired motor inhibition during REM sleep (REM sleep without atonia, RSWA). RBD is commonly associated with neurodegenerative disorders including Parkinsonisms, but is also reported in narcolepsy in up to 60% of patients. RBD in patients with narcolepsy is, however, a distinct phenotype with respect to other RBD patients and characterized also by absence of gender predominance, elementary rather than complex movements, less violent behavior and earlier age at onset of motor events, and strong association to narcolepsy with cataplexy/hypocretin deficiency. Patients with narcolepsy often present dissociated sleep features including RSWA, increased density of phasic chin EMG and frequent shift from REM to NREM sleep, with or without associated clinical RBD. Most patients with narcolepsy with cataplexy lack the hypocretin neurons in the lateral hypothalamus. Tonic and phasic motor activities in REM sleep and dream-enacting behavior are mostly reported in presence of cataplexy. Narcolepsy without cataplexy is a condition rarely associated with hypocretin deficiency. We proposed that hypocretin neurons are centrally involved in motor control during wakefulness and sleep in humans, and that hypocretin deficiency causes a functional defect in the motor control involved in the development of cataplexy during wakefulness and RBD/RSWA/phasic motor activity during REM sleep.     

Sleep‐related hypermotor epilepsy activated by rapid eye movement sleep

Most sleep‐related seizures occur during non‐rapid eye movement (NREM) sleep, particularly during stage changes. Sleep‐related hypermotor epilepsy (SHE) is a rare epileptic syndrome characterized by paroxysmal motor seizures, mainly arising from NREM sleep. Here, we report a patient with SHE who had seven seizures captured on video‐EEG‐polysomnography during REM sleep. Ictal semiology of this patient ranged from brief paroxysmal arousals to hypermotor seizures. On EEG‐polysomnography, the spontaneous arousals were more frequent during REM than NREM sleep, with a considerably higher arousal index in REM sleep (20/hour). While the reason for seizures during REM sleep in this patient is unclear, we speculate that the threshold and mechanisms of arousal during different sleep stages may be related to the occurrence of seizures. [Published with video sequences on www.epilepticdisorders.com ].     

Hallucinations and sleep-wake cycle in PD: a 24-hour continuous polysomnographic study

Twenty-four-hour ambulatory polysomnography was performed in 20 patients with PD who were having visual hallucinations (12 men and 8 women, mean age 70 +/- 6 years). Visual hallucinations were clearly related to daytime NREM sleep or nocturnal REM sleep in 33% of the instances. The data reinforce the hypothesis that neural mechanisms implicated in generating sleep and, in particular, in dream imagery play a role in the occurrence of visual hallucinations in PD.     

Wicket spikes during rapid eye movement sleep.

Wicket spikes correspond to a normal variant activity. They usually occur in adults over 50 years of age during drowsiness and light nonrapid eye movement (NREM) sleep. No data exist in the precise distribution of this activity during all the different sleep stages, particularly during rapid eye movement (REM) sleep. The authors report five observations of persistence of this activity during REM sleep. Only one patient was over 50 years of age. The authors found a predominant expression on one temporal side, but inconsistently on the left side (three on the left side versus two on the right side). Wicket spikes always persist in REM sleep. They have an identical morphology as drowsiness or stage 2 sleep. There were no changes in their location. The authors found no correlation with the tonic or phasic phases of REM sleep.     

Visual declarative memory is associated with non-rapid eye movement sleep and sleep cycles in patients with chronic non-restorative sleep

OBJECTIVE: Sleep contributes to processes of memory, but many questions still remain open. The aim of this study was to test the role of different aspects of sleep for memory performance in a group of patients with chronic non-restorative sleep. METHODS: Forty-two consecutive patients (mean age 40.3 years; 31 women) with non-restorative sleep were included. All subjects underwent polysomnography for diagnostic reasons and obtained the following diagnoses (International Classification of Sleep Disorders, ICSD): psychophysiological or idiopathic insomnia (N=18), paradoxical insomnia (N=13), mild hypersomnia (N=6), and dysthymic disorder (N=5). Patients with sleep-related breathing disorders or restless legs were not included. Prior to polysomnography on the second night and the next morning, neuropsychological tests were performed. Declarative memory was tested by the Rey-Osterrieth Complex Figure Test and a paired associative word list. Procedural learning was assessed by a mirror-tracing skill. RESULTS: Visual declarative memory performance was significantly associated with total sleep time, sleep efficiency, duration of non-rapid eye movement (NREM) sleep and number of NREM-REM sleep cycles, but not with specific measures of REM sleep or slow wave sleep. CONCLUSIONS: Further indications of a role of sleep, and in particular of NREM sleep and sleep organization, for visual declarative memory were found.     

Hallucinations, REM sleep, and Parkinson's disease: a medical hypothesis

BACKGROUND: Patients with PD can have disabling visual hallucinations associated with dopaminergic therapy. Sleep disorders, including vivid dreams and REM sleep with motor behaviors (RBD), are frequent in these patients. METHODS: The association of hallucinations and REM sleep both at night and during the day was examined in 10 consecutive nondemented patients with long-standing levodopa-responsive PD and hallucinations. Seven patients presented with paranoia and paranoid delusions. Overnight sleep recordings and standard multiple daytime sleep latency test were performed. The results were compared to those of 10 similar patients with PD not experiencing hallucinations. RESULTS: RBD was detected in all 10 patients with hallucinations and in six without. Although nighttime sleep conditions were similar in both groups, hallucinators tended to be sleepier during the day. Delusions following nighttime REM period and daytime REM onsets were observed in three and eight of the hallucinators, and zero and two of the others. Daytime hallucinations, coincident with REM sleep intrusions during periods of wakefulness, were reported only by hallucinators. Postmortem examination of the brain of one patient showed numerous Lewy bodies in neurons of the subcoeruleus nucleus, a region that is involved in REM sleep control. CONCLUSION: The visual hallucinations that coincide with daytime episodes of REM sleep in patients who also experience post-REM delusions at night may be dream imagery. Psychosis in patients with PD may therefore reflect a narcolepsy-like REM sleep disorder.     

What in sleep is for memory

Since the seminal research by Jenkins and Dallenbach in the 1920s, it has been well proven that sleep has a major effect on the memory of pre-sleep material. However, there is still sparse knowledge about exactly which features of sleep have the most impact. Studies which examined separately the role of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep provided largely controversial results and aroused harsh scientific debate, and the investigation of the link of specific sleep patterns to different memory systems (e.g. declarative vs. procedural) did not fully reconcile these inconsistencies. New research perspectives have been proposed in recent years to overcome the limits of the previous 'single state' approach. Psychological, neurophysiological and neuroanatomical data have recently suggested that NREM and REM sleep both play a part in memory consolidation. We here present the hypothesis that NREM and REM are complementary for memory processes during sleep, thanks to their close interaction within the NREM-REM cycle, and discuss experimental data which prove the critical role of the sleep cycle for the morning recall of verbal material.     

REM and NREM sleep as natural accompaniments of the evolution of warm-bloodedness

Divergence of primitive sleep into REM and NREM states is thought to have occurred in the nocturnal Triassic ancestors of mammals as a natural accompaniment of the evolution of warm-bloodedness. As ambient temperatures during twilight portions of primitive sleep traversed these evolving ancestors' core temperature, mechanisms of thermoregulatory control that employ muscle contractions became superfluous. The resulting loss of need for such contractions during twilight sleep led to muscle atonia. With muscle tone absent, selection favored the persistence of the fast waves of nocturnal activity during twilight sleep. Stimulations by these waves reinforce motor circuits at the increasing temperatures of evolving warm-bloodedness without leading to sleep-disturbing muscle contractions. By these and related interlinked adaptations, twilight sleep evolved into REM sleep. The daytime period of sleep became NREM sleep. The evolution of NREM and REM sleep following this scenario has implications for sleep's maintenance processes for long-term memories. During NREM sleep, there is an unsynchronized, uncoordinated stimulation and reinforcement of individual distributed component circuits of consolidated memories by slow wave potentials, a process termed ‘uncoordinated reinforcement’. The corresponding process during REM sleep is the coordinated stimulation and reinforcement of these circuits by fast wave potentials. This action temporally binds the individual component circuit outputs into fully formed memories, a process termed ‘coordinated reinforcement’. Sequential uncoordinated and coordinated reinforcement, that is, NREM followed by REM sleep, emerges as the most effective mechanism of long-term memory maintenance in vertebrates. With the evolution of this two-stage mechanism of long-term memory maintenance, it became adaptive to partition sleep into several NREM-REM cycles, thereby achieving a more lengthy application of the cooperative sequential actions.     

Concurrent occurrence of rapid eye movement with spindle burst during nocturnal sleep in mentally retarded children

Concurrence of REM and sleep spindle in 45 mentally retarded children (from 4 months to 8 years of age) was studied throughout nocturnal sleep, and the following results were obtained. (1) Twenty-five cases showed a single or burst of REMs during stage NREM with sleep spindles. (2) Twenty-nine cases showed sleep spindles at the beginning or toward the end of stage REM sleep. (3) No significant difference in DQ was found between the subjects with and without REMs during stage NREM sleep. The former subjects, however, had more normal clinical EEGs than the latter. (4) No significant difference in DQ or clinical EEG classification was revealed between the subjects with REMs during stage NREM sleep and those with spindles during stage REM sleep. (5) It was concluded that the concurrence of REM and sleep spindle during stage NREM is a useful sign for early diagnosis of mental retardation.     

Evidence for 2-stage models of sleep and memory: Learning-dependent changes in spindles and theta in rats

What processes are involved in the formation of enduring memory traces? Sleep has been proposed to play a role in memory consolidation and the present study provides evidence to support 2-stage models of sleep and memory including both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Previous research has shown REM sleep increases following avoidance learning and memory is impaired if REM deprivation occurs during these post-training periods indicating that REM sleep may have a role in memory consolidation processes. These discrete post-training periods have been termed REM sleep windows (RSWs). It is not known whether the electroencephalogram has unique characteristics during the RSW. Further investigation of the RSW was one of the primary goals of this study. We investigated the epidural-recorded electrophysiological learning-related changes following avoidance training in rats. Theta power increased in the learning group during the RSW, suggesting that theta is involved in memory consolidation during this period. Sleep spindles subsequently increased in slow wave sleep (SWS). The results suggest that both NREM and REM sleep are involved in sleep-dependent memory consolidation, and provide support for existing 2-stage models. Perhaps first theta increases to organize and consolidate material via hippocampal–neocortical dialogue, followed by subsequent refinement in the cortex by spindles during SWS.     

Effects of rapid eye movement sleep deprivation on fear extinction recall and prediction error signaling

In a temporal difference learning approach of classical conditioning, a theoretical error signal shifts from outcome deliverance to the onset of the conditioned stimulus. Omission of an expected outcome results in a negative prediction error signal, which is the initial step towards successful extinction and may therefore be relevant for fear extinction recall. As studies in rodents have observed a bidirectional relationship between fear extinction and rapid eye movement (REM) sleep, we aimed to test the hypothesis that REM sleep deprivation impairs recall of fear extinction through prediction error signaling in humans. In a three-day design with polysomnographically controlled REM sleep deprivation, 18 young, healthy subjects performed a fear conditioning, extinction and recall of extinction task with visual stimuli, and mild electrical shocks during combined functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. Compared to the control group, the REM sleep deprivation group had increased SCR scores to a previously extinguished stimulus at early recall of extinction trials, which was associated with an altered fMRI time-course in the left middle temporal gyrus. Post-hoc contrasts corrected for measures of NREM sleep variability also revealed between-group differences primarily in the temporal lobe. Our results demonstrate altered prediction error signaling during recall of fear extinction after REM sleep deprivation, which may further our understanding of anxiety disorders in which disturbed sleep and impaired fear extinction learning coincide. Moreover, our findings are indicative of REM sleep related plasticity in regions that also show an increase in activity during REM sleep.     

Relationship between hallucinations, delusions, and rapid eye movement sleep behavior disorder in Parkinson's disease.

Psychotic symptoms are the main and the most disabling "nonmotor" complications of Parkinson's disease (PD), the pathophysiology of which is poorly recognized. Polysomnographic studies have shown a relationship between visual hallucinations and rapid eye movement (REM) sleep. The objective of this study is to clarify the relationship between psychotic symptoms and REM sleep behavior disorder (RBD) in PD. In a Parkinson's disease outpatient unit, 289 consecutive subjects with idiopathic PD were administered (in the period from January to December 2002) a multiple-choice questionnaire and structured interview on sleep and mental disorders. RBD was diagnosed in accordance with the minimal diagnostic criteria of the International Classification of Sleep Disorders. Hallucinations and delusional disorders were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-IV criteria. The presence or absence of psychotic symptoms, of RBD, and of daytime sleepiness, as well as motor status, cognitive status, and mood were assessed. Approximately 32% (n = 92) of the subjects presented with psychotic disorders; 30% (n = 86) had experienced hallucinations; 2% (n = 6) had delusions without hallucinations. Sixty-two (72%) hallucinators reported nocturnal hallucinations. A total of 6.6% (n = 19) of the subjects complained of a delusional disorder. There were 26.6% (n = 77) of subjects who presented with RBD: 28 (36%) with onset before and 49 (63%) with onset after PD diagnosis. The presence of RBD was associated with an increased risk of manifesting hallucinations and delusions (odds ratio [OR], 2.73). Other independent clinical factors found to have an effect on psychotic disorders were cognitive impairment (OR, 3.92), disease duration (OR, 2.46), advanced age (OR, 2.34), and severity of motor symptoms (OR, 2.06). These results suggest that RBD is widely associated with psychosis in PD.     

Evolutionary approaches to understanding sleep

A major controversy over REM sleep's role in memory processing may owe to inadequate allowances for the highly conservative nature of evolutionary adaptations. The controversy hinges on whether NREM sleep, alone, retains primitive memory processing capabilities. The selective pressure for primitive sleep, is thought to have been the need to obviate conflicts between enormous neural processing requirements of complex visual analysis and split-second control of movements, on the one hand, and memory processing, on the other. The most efficient memory processing during mammalian and avian sleep appears to be a two-step process: synapses in individual component circuits of events are reinforced primarily by slow brain waves during NREM sleep, with the reinforced components temporally bound by fast waves, and manifested as dreams, during REM sleep. This dual action could account for partitioning of sleep periods into multiple NREM-REM cycles. It is proposed that in the absence of REM sleep, all needed memory processing can be accomplished by NREM sleep, alone, though less efficiently. Many symptoms of fatal familial insomnia are attributed to subnormal nightly reinforcement of brain circuitry because of almost total loss of sleep, and compensatory responses thereto during waking. During this disorder, sensory circuitry seemingly is spared by virtue of its supernormal reinforcement during almost continuous waking. Contrariwise, sparing of an adult's 'higher faculties' in encephalitis lethargica appears to owe to supernormal circuit reinforcement during almost continuous sleep.     

Pontine control of rapid eye movement sleep and fear memory

Aims

We often experience dreams of strong irrational and negative emotional contents with postural muscle paralysis during rapid eye movement (REM) sleep, but how REM sleep is generated and its function remain unclear. In this study, we investigate whether the dorsal pontine sub-laterodorsal tegmental nucleus (SLD) is necessary and sufficient for REM sleep and whether REM sleep elimination alters fear memory.

Methods

To investigate whether activation of SLD neurons is sufficient for REM sleep induction, we expressed channelrhodopsin-2 (ChR2) in SLD neurons by bilaterally injecting AAV1-hSyn-ChR2-YFP in rats. We next selectively ablated either glutamatergic or GABAergic neurons from the SLD in mice in order to identify the neuronal subset crucial for REM sleep. We finally  investigated the role of REM sleep in consolidation of fear memory using rat model with complete SLD lesions.

Results

We demonstrate the sufficiency of the SLD for REM sleep by showing that photo-activation of ChR2 transfected SLD neurons selectively promotes transitions from non-REM (NREM) sleep to REM sleep in rats. Diphtheria toxin-A (DTA) induced lesions of the SLD in rats or specific deletion of SLD glutamatergic neurons but not GABAergic neurons in mice completely abolish REM sleep, demonstrating the necessity of SLD glutamatergic neurons for REM sleep. We then show that REM sleep elimination by SLD lesions in rats significantly enhances contextual and cued fear memory consolidation by 2.5 and 1.0 folds, respectively, for at least 9 months. Conversely, fear conditioning and fear memory trigger doubled amounts of REM sleep in the following night, and chemo-activation of SLD neurons projecting to the medial septum (MS) selectively enhances hippocampal theta activity in REM sleep; this stimulation immediately after fear acquisition reduces contextual and cued fear memory consolidation by 60% and 30%, respectively.

Conclusion

SLD glutamatergic neurons generate REM sleep and REM sleep and SLD via the hippocampus particularly down-regulate contextual fear memory.     

EEG activities during elicited sleep onset REM and NREM periods reflect different mechanisms of dream generation. Electroencephalograms. Rapid eye movement.

OBJECTIVE: To be the first to compare EEG power spectra during sleep onset REM periods (SOREMP) and sleep onset NREM periods (NREMP) in normal individuals and relate this to dream appearance processes underlying these different types of sleep periods. METHODS: Eight healthy undergraduates spent 7 consecutive nights in the sleep lab including 4 nights for SOREMP elicitation using the Sleep Interruption Technique. This enabled us to control preceding sleep processes between SOREMP and NREMP. EEG power spectra when participants did and did not report 'dreams' were compared between both types of sleep. Sleep stages, subjective measurements including dream property scores, sleepiness, mood, and tiredness after awakenings were also examined to determine their consistency with EEG findings. RESULTS: Increased alpha EEG activities (11.72-13.67 Hz) observed mainly in the central area were related to the absence of SOREMP dreams and appearance of NREMP dreams. Analyses of sleep stages combining two studies (16 participants) also supported the Fast Fourier Transform findings, showing that when dreams were reported there were decreased amounts of stage 2 and increased stage REM in SOREMP and increased stage W in NREMP. SOREMP dreams were more bizarre than NREMP dreams. Participants felt more tired after SOREMP with dreams than without dreams, while the opposite was observed after NREMP episodes. CONCLUSIONS: EEG power spectra patterns reflected different physiological mechanisms underlying generation of SOREMP and NREMP dreams. The same relationships were also reflected by sleep stage analyses as well as subjective measurements including dream properties and tiredness obtained after awakenings. This study not only supports the hypothesized relationships between REM mechanisms and REM dreams as well as arousal processes and NREM dreams, it also provides a new perspective to dream research due to its unique techniques to awaken participants and collect REM dreams during experimentally induced SOREMP.     

Heart rate variability: sleep stage,time of night,and arousal influences

Spectral analysis was used to assess heart rate variability in consecutive 5-min epochs during the night in 12 normal adults. Simultaneous time coding of EEG and digitized EKG allowed examination of heart rate variability as a function of sleep stage, time of night and presence of EEG arousal. The results replicated previous studies in showing increases in high frequency components and decreases in low frequency components of heart rate variability across NREM sleep stages and opposite changes in REM sleep and wake. These results are consistent with sympathetic nervous system activation during REM sleep and wake periods. The shift in heart rate variability seen during REM sleep began in NREM sleep several minutes prior to standardly scored REM and often continued beyond the end of REM sleep. EEG arousals during Stage 2 and to some extent REM sleep were also associated with changes in heart rate variability which were consistent with sympathetic activation. An examination of beat to beat intervals in proximity to EEG arousals showed heart rate acceleration at least 10 beats prior to the EEG arousal. The arousal data along with Stage 2 sleep transition data support the contention that increases in central nervous system sympathetic activity precede and possibly play a role in the initiation of REM sleep and arousals during sleep.     

Sympathetic and cardiovascular changes during sleep in narcolepsy with cataplexy patients

ObjectiveNeural mechanisms underlying sleep-onset rapid eye movement (REM) periods (SOREMPs) in narcolepsy and the role of hypocretin in driving sympathetic changes during sleep are misunderstood. We aimed to characterize autonomic changes during sleep in narcolepsy with cataplexy (NC) patients to clarify the nature of SOREMP events and the effect of hypocretin deficiency on sympathetic activity during sleep.MethodsWe observed 13 hypocretin-deficient NC patients and five healthy controls who underwent nocturnal video-polysomnography (v-PSG) with blood pressure (BP) recording, heart rate (HR), skin sympathetic activity (SSA), and muscle sympathetic nerve activity (MSNA) from the peroneal nerve by microneurography.ResultsCompared to wake, control participants displayed a progressive significant decrease of BP and sympathetic activities during nonrapid eye movement (NREM) sleep and an increase of autonomic activity during REM sleep, as expected. NC patients showed: (1) a decrease of sympathetic activities during SOREMP comparable to NREM sleep stage 1 (N1) but in contrast to the increased activity typical of REM sleep; and (2) physiologic sympathetic change during the following sleep stages with a progressive decrease during NREM sleep stage 2 (N2) and NREM sleep stage 3 (N3) and a clear increase in REM sleep, though BP did not show the physiologic decrease during sleep (nondipper pattern).ConclusionsSOREMPs in NC patients lack the sympathetic activation occurring during physiologic REM sleep, thus suggesting a dissociated REM sleep condition. In addition, our data indicated that hypocretin plays a limited role in the regulation of sympathetic changes during sleep.     

Varying expressions of alerting mechanisms in wakefulness and across sleep states.

Alerting stimuli, such as intense tones, presented to cats in wakefulness (W) elicit the orienting response (OR) and/or the acoustic startle reflex (ASR) in conjunction with elicited ponto-geniculo-occipital waves (PGOE) from the lateral geniculate body (LGB) and elicited waves from the thalamic central lateral nucleus (CLE). Alerting stimuli presented during rapid eye movement sleep (REM) and non-rapid eye movement sleep (NREM) also elicit PGOE. We presented tones in W, REM and NREM to determine whether CLE could be obtained in sleep and to examine the patterns of responsiveness of PGOE and CLE across behavioral states. Also, we recorded ASR and OR and compared the response patterns of behavioral and central correlates of alerting. The subjects were 7 cats; all exhibited spontaneously occurring waves in LGB and CL. All cats exhibited PGOE and 5 cats exhibited CLE in W, REM and NREM. PGOE and CLE showed less evidence of habituation than did ASR and OR. The pattern of responsiveness of CLE across behavioral states was different from that found for PGOE, and spontaneous CL waves were much rarer than the LGB waves. ASR was elicited in 5 cats during W trials, and in 3 cats during REM trials. OR habituated rapidly in W and did not occur in REM and NREM. The data indicate that central mechanisms of alerting function in sleep states as well as in W and suggest that CLE and PGOE reflect activity in mechanisms underlying cortical desynchronization and visual processes which may act in concert during alerting.     

Slowing of electroencephalogram in rapid eye movement sleep behavior disorder

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by a loss of atonia and an increase in phasic muscle activity during REM sleep, leading to complex nocturnal motor behaviors. Brainstem structures responsible for the pathogenesis of RBD are also implicated in cortical activation. To verify the hypothesis that electroencephalogram (EEG) activation will be impaired in RBD, we performed quantitative analyses of waking and REM sleep EEG in 15 idiopathic RBD patients and 15 age- and gender-matched healthy subjects. During wakefulness, RBD patients showed a considerably higher theta power in frontal, temporal, and occipital regions with a lower beta power in the occipital region. The dominant occipital frequency was significantly lower in RBD. During REM sleep, beta power in the occipital region was lower in RBD. This study shows for the first time an impaired cortical activation during both wakefulness and REM sleep in idiopathic RBD, despite an absence of changes on sleep architecture compared with controls. EEG slowing in these patients may represent an early sign of central nervous system dysfunction, perhaps paralleled by subclinical cognitive deficits. The topographical distribution of EEG slowing and possible pathophysiological mechanisms are discussed in light of the known association between RBD and neurodegenerative disorders.