Visual hallucinations as REM sleep behavior disorders in patients with Parkinson's disease.

To clarify whether visual hallucinations in patients with Parkinson's disease (PD) are related to rapid eye movement (REM) sleep, nocturnal polysomnographic variables were compared between a group with hallucinations (hallucinators, n = 14) and a group without hallucinations (nonhallucinators, n = 8). A multiple sleep latency test (MSLT) was performed on 3 hallucinators, and the content of dreams during daytime REM sleep was investigated. The efficacy of clonazepam, a standard treatment choice for REM sleep behavior disorders, was investigated in 8 hallucinators. Nocturnal polysomnograms of the hallucinators showed a higher amount of stage 1-REM sleep with tonic electromyogram (stage 1-REM) than the nonhallucinators, and the reported occurrences of nocturnal hallucinations corresponded with the periods of stage REM or stage 1-REM in most hallucinators. The frequency of sleep onset REM periods (SOREMP) on the MSLT were pathologically high in the hallucinators, and the content of the dreams during the MSLT period was quite similar to their hallucinations. During clonazepam treatment, the frequency of hallucinatory symptoms decreased in 5 of 8 hallucinators. These results indicate that visual hallucinations in PD are likely to be related to a REM sleep disorder manifested as the appearance of both stage 1-REM during the night and SOREMP in the daytime.     

Do all mammals dream?

The presence of dreams in human sleep, especially in REM sleep, and the detection of physiologically similar states in mammals has led many to ponder whether animals experience similar sleep mentation. Recent advances in our understanding of the anatomical and physiological correlates of sleep stages, and thus dreaming, allow a better understanding of the possibility of dream mentation in nonhuman mammals. Here, we explore the potential for dream mentation, in both non-REM and REM sleep across mammals. If we take a hard-stance, that dream mentation only occurs during REM sleep, we conclude that it is unlikely that monotremes, cetaceans, and otariid seals while at sea, have the potential to experience dream mentation. Atypical REM sleep in other species, such as African elephants and Arabian oryx, may alter their potential to experience REM dream mentation. Alternatively, evidence that dream mentation occurs during both non-REM and REM sleep, indicates that all mammals have the potential to experience dream mentation. This non-REM dream mentation may be different in the species where non-REM is atypical, such as during unihemispheric sleep in aquatic mammals (cetaceans, sirens, and Otariid seals). In both scenarios, the cetaceans are the least likely mammalian group to experience vivid dream mentation due to the morphophysiological independence of their cerebral hemispheres. The application of techniques revealing dream mentation in humans to other mammals, specifically those that exhibit unusual sleep states, may lead to advances in our understanding of the neural underpinnings of dreams and conscious experiences.     

溴麦角隐亭诱导的猴幻想行为的生理学特性(英文)

目的溴隐亭及多巴胺受体D2激动剂会影响除人以外其它灵长类动物的一系列行为,特别是与运动和心理活动相关的行为,比如动物会表现出抑制性行为及幻觉样行为。除药物外,快速眼动睡眠(REM)机制的紊乱也可导致幻觉。打乱清醒、REM及非快速眼动睡眠(NREM)的规律可引起一系列精神病症状。方法当动物处于清醒,NREM和REM及药物导致的类精神病状态时,同时记录五个皮层脑区的听觉诱发电位,从而研究对比不同状态下听觉诱发电位的变化。结果在幻觉状态及REM期,前额叶背外侧皮层记录到的潜伏期为250ms的诱发电位成分出现波峰到基线的相位翻转(PBA250),说明幻觉状态及REM在前额叶背外侧皮层有类似的调节机制。结论在前额叶背外侧皮层记录到的N250可以用来判断幻觉样行为是否出现,这表明前额叶背外侧皮层可能同幻觉样行为最相关。     

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.     

溴麦角隐亭诱导的猴幻想行为的生理学特性

目的 溴隐亭及多巴胺受体D2激动剂会影响除人以外其它灵长类动物的一系列行为,特别是与运动和心理活动相关的行为,比如动物会表现出抑制性行为及幻觉样行为。除药物外,快速眼动睡眠（REM）机制的紊乱也可导致幻觉。打乱清醒、REM及非快速眼动睡眠（NREM）的规律可引起一系列精神病症状。方法 当动物处于清醒,NREM和REM及药物导致的类精神病状态时,同时记录五个皮层脑区的听觉诱发电位,从而研究对比不同状态下听觉诱发电位的变化。结果 在幻觉状态及REM期,前额叶背外侧皮层记录到的潜伏期为250ms的诱发电位成分出现波峰到基线的相位翻转（PBA250）,说明幻觉状态及REM在前额叶背外侧皮层有类似的调节机制。结论 在前额叶背外侧皮层记录到的N250可以用来判断幻觉样行为是否出现,这表明前额叶背外侧皮层可能同幻觉样行为最相关。     

Rapid eye movement sleep,non-rapid eye movement sleep,dreams, and hallucinations

After the discovery of rapid eye movement (REM) sleep in 1953, oneiric activity was long thought to be associated uniquely with REM sleep. Subsequent evaluation of sleep in humans combining neurophysiologic, psychophysiologic, and, more recently, functional neuroimaging investigations, has instead shown that dreaming also occurs during non-REM (NREM) sleep. It has been documented that hallucinatory activity during sleep is a normal phenomenon that is not constant throughout the night but increases toward morning when it tends to become present to the same extent in REM and NREM sleep. The role of sleep mechanisms in the generation of visual hallucinations is well-recognized in narcolepsy in the case of hypnagogic hallucinations, which are thought to derive from a REM-dissociation state in which dream imagery intrudes into wakefulness. Similar mechanisms have been hypothesized to play a role in the physiopathogenesis of visual hallucinations in various neuropsychiatric disorders. Furthermore, a growing body of evidence indicates that not only REM but also NREM processes, such as arousal-related processes, may play a role in the physiopathogenesis of hallucinations in the aforementioned disorders. The role of these processes has been most extensively documented in visual hallucinations occurring in the context of delirium tremens and Parkinson’s disease.     

Influence of hypnogenic brain areas on wakefulness- and rapid-eye-movement sleep-related neurons in the brainstem of freely moving cats

Rapid-eye-movement (REM) sleep is normally preceded by non-REM sleep; however, every non-REM sleep episode is not followed by REM sleep. It has been proposed that, for the regulation of REM sleep, the brain areas modulating waking and non-REM sleep are likely to communicate with neurons promoting REM sleep. The former has been reported earlier, and in this study the latter has been investigated. Under surgical anaesthesia, cats were prepared for electrophysiological recording of sleep-wakefulness and electrical stimulation of caudal brainstem as well as preopticoanterior hypothalamic hypnogenic areas. Insulated microwires of 25-32 microm were used to record 52 single neuronal activities from the brainstem along with bipolar electroencephalogram, electromyogram, electrooculogram, and pontogeniculooccipital waves in freely moving, normally behaving cats. The neurons were classified into five groups based on changes in firing rates associated with different sleep-waking states compared with quiet wakefulness. Thereafter, the responses of these neurons to 1-Hz stimulation of the two non-REM sleep-promoting areas were studied. At the end of experiment, the stimulating and recording sites were histologically identified. It was observed that, among the affected neurons, the caudal brainstem non-REM sleep-promoting area excited more REM-on neurons, whereas the preopticoanterior hypothalamus hypnogenic area inhibited more awake-active neurons. Thus, the results suggest that, at the single neuronal level, the caudal brainstem non-REM sleep-modulating area, rather than the preopticoanterior hypothalamic hypnogenic area in the brain, plays a modulatory role in triggering REM sleep initiation at a certain depth of sleep.     

The effect of physostigmine on normal human sleep and dreaming.

Physostigmine, an anticholinesterase that increases the action of brain acetylcholine, induces rapid eye movement (REM) sleep in normal humans. In this study we show that man dreams during physostigmine-induced REM sleep. Seventeen normal volunteers were pretreated with methscopolamine and received one intravenous infusion per night of either placebo or physostigmine either ten or 35 minutes after sleep onset. Subjects were awakened at specific times after infusion and interviewed regarding any sleep mentation prior to awakening. Results indicated that dreaming occurred during physostigmine-induced REM periods but that physostigmine did not alter mentation during non-REM sleep. These dreams were similar to spontaneous REM sleep dreams in content, vividness, unusualness, and emotionality.     

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.     

Short-term effects of fluoxetine and trifluoromethylphenylpiperazine on electroencephalographic sleep in the rat

Fluoxetine and trifluoromethylphenylpiperazine (TFMPP) were studied for their short-term effects on electroencephalographic sleep in male rats. Following single injection, each drug produced a sizeable, dose-related suppression of rapid-eye-movement (REM) sleep that persisted for 4-5 h (fluoxetine, 0.625-5 mg/kg; TFMPP, 0.10-1.25 mg/kg). TFMPP also consistently increased non-REM (NREM) sleep during the second hour after drug injection, though this effect was not dose-related (it was seen at all doses tested). Fluoxetine produced small effects on NREM sleep that varied non-systematically with dose and time after drug injection. TFMPP, but not fluoxetine, also increased at all doses the number of delta waves per minute of NREM sleep in the second hour. A structural analog of TFMPP that is inactive at serotonin (5-HT) receptors [4-(m-trifluoromethylphenyl)piperadine; LY97117] was also tested, and found to be devoid of effects on NREM and REM sleep. Both fluoxetine (a 5-HT reuptake blocker) and TFMPP (a 5-HT agonist) enhance transmission across 5-HT synapses, though by different mechanisms. Because they have the common effect of suppressing REM sleep, and in a dose-related manner, the data support the notion that 5-HT neurons in the brain, when active, can suppress REM sleep.     

Inter-relationship of hallucinations and dreams in spontaneously hallucinating patients

Summary Inter-relationship of hallucinations and dreams, the psychological function of dreaming and hallucinating, and their possible equivalence are considered in terms of psychoanalytic theory. Seven patients from the wards of a large city psychiatric hospital were interviewed in order to elicit their experience of hallucinations contrasted with their dream experience. Five had spontaneous auditory and visual hallucinations; one somaesthetic; in one the hallucinations were amphetamine-induced. All hallucinators recalled dreams with varying degrees of vividness. Four reported being awakened by their hallucinations as exteroceptive stimuli. Only one, the chronic amphetamine abuser, indicated that his hallucinations had entered his dreams: He had paranoid dreams akin to a continuation of an amphetamine trip.Hallucinators maintain distinction between their dreams and hallucinations, but do not definitely differentiate the latter from their normal perceptions. Although hallucinations may interrupt sleep and wake the dreamer, dreams are not pervaded by hallucinations. The possibility that dreams may partake of the hallucinatory content requires further investigation. Hallucinogenic drugs may potentiate penetration of dreams by waking-state hallucinations as part of the day residue.Based on part of an elective course, Phenomenology of Spontaneous Hallucination, conducted by Drs. Kass and Jenkins at New York University School of Medicine, Department of Psychiatry and Neurology, January-February, 1968.     

Extracellular serotonin levels in the medullary reticular formation during normal sleep and after REM sleep deprivation

Rapid eye movement (REM) sleep is hypothesized to result from the activity of REM sleep-generating and REM sleep-inhibiting neurons. The serotoninergic (5-HT) neurons of the dorsal raphe nucleus (DRN) represents one such population of REM-sleep inhibiting neurons since they are silent during REM sleep. Consistent with the decrease in activity of 5-HT neurons, the brain extracellular levels of 5-HT are lower during REM sleep compared to wakefulness. It is not known whether serotonin release is also reduced as a consequence of REM sleep rebound. Using microdialysis sampling coupled to HPLC–ECD, we measured the extracellular levels of 5-HT and its metabolite (5-HIAA) in the medial medullary reticular formation (mMRF) of freely behaving rats during normal sleep, REM sleep deprivation as well as during REM sleep rebound. We found that the levels 5-HT and 5-HIAA were significantly decreased by REM sleep deprivation. The reduction of 5-HT release was maintained during REM sleep rebound but the extracellular level of its main metabolite was increased. In addition, even during REM sleep rebound, 5-HT release during sleep was low compared to wakefulness. Taken together these data support the permissive role of 5-HT neurotransmission for REM sleep expression.     

Effect of sleep deprivation on sleep and EEG power spectra in the rat

EEG power spectra of the rat were computed for consecutive 4-s epochs of the daily light period and matched with the scores of the vigilance states. Sleep was characterized by a progressive decline of low frequency spectral values (i.e. slow wave activity) in non-rapid eye movement (non-REM) sleep, and a progressive increase in the amount of REM sleep. During recovery from 24-h total sleep deprivation (TSD) the following changes were observed: an increase of slow wave activity in non REM sleep with a persisting declining trend; an enhancement of theta activity (7.25-10.0 Hz) both in REM sleep and waking; a decrease of non-REM sleep and an increase of REM sleep. In addition, a slow wave EEG pattern prevailed in the awake and behaving animal during the initial recovery period. In selective sleep deprivation paradigms, either REM sleep or slow wave activity in non-REM sleep was prevented during a 2-h period following upon 24-h TSD. During both procedures, non-REM sleep spectra in the lowest frequency band showed no increase. There was no evidence for a further enhancement of slow wave activity after its selective deprivation. The results indicate that: (1) slow wave activity in non-REM sleep and theta activity in REM sleep may reflect sleep intensity; and (2) REM sleep and active waking, the two states with dominant theta activity, may be functionally related.     

Neurological interpretation of dreams]

Cerebral cortical activity is constant throughout the entire human life, but substantially changes during the different phases of the sleep-wake cycle (wakefulness, non-REM sleep and REM sleep), as well as in relation to available information. In particular, perception of the environment is closely linked to the wake-state, while during sleep perception turns to the internal domain or endogenous cerebral activity. External and internal information are mutually exclusive. During wakefulness a neuronal mechanism allows attention to focus on the environment whereas endogenous cortical activity is ignored. The opposite process is provided during sleep. The function external attention-internal attention is coupled with the two modes of brain function during wakefulness and during sleep, providing two possible cortical status: thinking and dreaming. Several neurological processes may influence the declaration of the three states of being or may modify their orderly oscillation through the sleep-wake cycle. In addition, endogenous information and its perception (dreams) may be modified. Disturbances of dreaming may configurate in different general clinical scenarios: lack of dreaming, excess of dreaming (epic dreaming), paroxysmal dreaming (epileptic), nightmares, violent dreaming, daytime-dreaming (hallucinations), and lucid dreaming. Sensorial deprivation, as well as the emergence of internal perception may be the underlying mechanism of hallucinations. The probable isomorphism between hallucinations and dreaming is postulated, analyzed and discussed.     

Activity of nucleus raphe pallidus neurons across the sleep-waking cycle in freely moving cats

The activity of serotonin-containing nucleus raphe pallidus (RPA) units was recorded by means of movable 32 or 62 μm diameter insulated nichrome wires in freely moving cats. RPA units displayed a slow, rhythmic discharge rate during waking (X¯= 5.3spikes/s) and showed no significant change in activity during slow-wave sleep. However, these neurons showed a large decrease in activity during REM sleep (X¯= 1.2spikes/s). In contrast with results from studies on serotonin-containing nucleus raphe dorsalis units, RPA neurons showed no relationship to the occurrence of sleep spindles, and were not inhibited by low doses of LSD.     

Relation of pontine choline acetyltransferase immunoreactive neurons with cells which increase discharge during REM sleep

The purpose of this study was to determine whether neurons in the medial pontine reticular formation with high discharge rates during REM sleep could be localized in regions of the brainstem having neurons displaying choline acetyltransferase immunoreactivity. Six cats were implanted with sleep recording electrodes and microwires to record extracellular potentials of neurons in the pontine reticular formation. Single-units with a S:N ratio greater than 2:1 were recorded for at least two REM sleep cycles. A total of 49 units was recorded from the pontine reticular formation at medial-lateral planes ranging from 0.8 to 3.7 mm. The greatest proportion of the units (28.6%) showed highest discharge during active waking and phasic REM sleep compared to quiet waking, non-REM sleep, transition into REM sleep or quiet REM sleep periods. A percentage (20.4%) of the cells had high discharge associated with phasic REM sleep periods while 8.2% of the cells showed a progressive increase in discharge from waking to REM sleep. Subsequent examination of the distribution of choline acetyltransferase immunoreactive cells in the PRF revealed that cells showing high discharge during REM sleep were not localized near presumed cholinergic neurons. Indeed, we did not find any ChAT immunoreactive somata in the medial PRF, an area which has traditionally been implicated in the generation of REM sleep. These results suggest that while increased discharge of PRF cells may be instrumental to REM sleep generation, these cells are not cholinergic.     

Dream experience during REM and NREM sleep of patients with complex partial seizures

This study examined the effectiveness of the cognitive processes underlying dreaming in patients with complex partial seizures (CPS), by assessing the frequency of recall and the structural organization of dreams reported after awakenings provoked alternately during REM and stage 2 NREM sleep on 12 cognitively unimpaired CPS-patients (six with epileptic focus in the right hemisphere and six in the left one). Each patient was recorded for three consecutive nights, respectively, for adaptation to the sleep laboratory context, for polysomnography and for dream collection. The frequency of dream recall was lower after stage 2 NREM sleep than REM sleep, regardless of the side of epileptic focus, while the length and structural organization of dreams did not significantly differ in REM and NREM sleep. However, the length of story-like dreams was influenced by global cognitive functioning during REM sleep. These findings indicate that in CPSs-patients the elaboration of dream experience is maintained in both REM and NREM sleep, while the access to information for conversion into dream contents and the consolidation of dream contents is much less effective during NREM rather than during REM sleep. Further studies may distinguish between these two possibilities and enlighten us as to whether the impaired memory functioning during NREM sleep is a side effect of anticonvulsant treatment.     

Locus Coeruleus Acid-Sensing Ion Channels Modulate Sleep–Wakefulness and State Transition from NREM to REM Sleep in the Rat

The locus coeruleus (LC) is one of the essential chemoregulatory and sleep–wake (S–W) modulating centers in the brain. LC neurons remain highly active during wakefulness, and some implicitly become silent during rapid eye movement (REM) sleep. LC neurons are also involved in CO₂-dependent modulation of the respiratory drive. Acid-sensing ion channels (ASICs) are highly expressed in some brainstem chemosensory breathing regulatory areas, but their localization and functions in the LC remain unknown. Mild hypercapnia increases the amount of non-REM (NREM) sleep and the number of REM sleep episodes, but whether ASICs in the LC modulate S–W is unclear. Here, we investigated the presence of ASICs in the LC and their role in S–W modulation and the state transition from NREM to REM sleep. Male Wistar rats were surgically prepared for chronic polysomnographic recordings and drug microinjections into the LC. The presence of ASIC-2 and ASIC-3 in the LC was immunohistochemically characterized. Microinjections of amiloride (an ASIC blocker) and APETx2 (a blocker of ASIC-2 and -3) into the LC significantly decreased wakefulness and REM sleep, but significantly increased NREM sleep. Mild hypercapnia increased the amount of NREM and the number of REM episodes. However, APETx2 microinjection inhibited this increase in REM frequency. These results suggest that the ASICs of LC neurons modulate S–W, indicating that ASICs could play an important role in vigilance-state transition. A mild increase in CO₂ level during NREM sleep sensed by ASICs could be one of the determinants of state transition from NREM to REM sleep.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12264-020-00625-0.     

A function for REM sleep: regulation of noradrenergic receptor sensitivity

We hypothesize that REM sleep serves to upregulate and/or prevent downregulation of brain norepinephrine (NE) receptors. This hypothesis is based on the following observations:

1. (1) NE neurons of the locus coeruleus (LC) are tonically active in waking and non-REM sleep, but the entire population of LC NE neurons is inactive during REM sleep.

2. (2) Continuous presence of NE or adrenoceptor agonists downregulates NE receptors, while a reduction in NE availability upregulates these receptors.

3. (3) The effects of REM sleep deprivation are similar to those of NE receptor downregulation. Recent biochemical studies of NE receptor sensitivity provide strong experimental support for this hypothesis. The functional consequence of enhanced NE receptor ‘tone’ brought about by REM sleep would be improved signal processing in diverse brain systems, thus endowing the organism with a selective advantage. This hypothesis makes a number of specific predictions which can be tested with currently available techniques, and suggests new ways of understanding the evolution and postnatal development of REM sleep.