The revised monoamine hypothesis: Mechanism of antidepressant treatment in the context of behavior

The temporal restoration of brain monoamines in the synaptic cleft due to MAO inhibition or by blocking catecholamine reuptake is only the the first step on the way to recovery from depression. The second and crucial step represents the feedback system, which can provide the continuous restoration of brain monoamines in the context of free search behavior. This feedback system on the one hand helps to overcome depression and on the other hand causes the hyposensitivity of the postsynaptic catecholamine (CA) receptors, due to the increased activity of the brain CA system. According to the search activity concept, REM sleep in the healthy subject, being a part of the same feedback system, restores brain monoamines. The mechanism of REM sleep deprivation in the treatment of depression is discussed in the context of this feedback system.     

The case against memory consolidation in REM sleep

We present evidence disputing the hypothesis that memories are processed or consolidated in REM sleep. A review of REM deprivation (REMD) studies in animals shows these reports to be about equally divided in showing that REMD does, or does not, disrupt learning/memory. The studies supporting a relationship between REM sleep and memory have been strongly criticized for the confounding effects of very stressful REM deprivation techniques. The three major classes of antidepressant drugs, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors (SSRIs), profoundly suppress REM sleep. The MAOIs virtually abolish REM sleep, and the TCAs and SSRIs have been shown to produce immediate (40-85%) and sustained (30-50%) reductions in REM sleep. Despite marked suppression of REM sleep, these classes of antidepressants on the whole do not disrupt learning/memory. There have been a few reports of patients who have survived bilateral lesions of the pons with few lingering complications. Although these lesions essentially abolished REM sleep, the patients reportedly led normal lives. Recent functional imaging studies in humans have revealed patterns of brain activity in REM sleep that are consistent with dream processes but not with memory consolidation. We propose that the primary function of REM sleep is to provide periodic endogenous stimulation to the brain which serves to maintain requisite levels of central nervous system (CNS) activity throughout sleep. REM is the mechanism used by the brain to promote recovery from sleep. We believe that the cumulative evidence indicates that REM sleep serves no role in the processing or consolidation of memory.     

Hemispheric lateralization of the EEG during wakefulness and REM sleep in young healthy adults

EEG recordings confirm hemispheric lateralization of brain activity during cognitive tasks. The aim of the present study was to investigate spontaneous EEG lateralization under two conditions, waking and REM sleep. Bilateral monopolar EEG was recorded in eight participants using a 12-electrode montage, before the night (5 min eyes closed) and during REM sleep. Spectral analysis (0.75-19.75 Hz) revealed left prefrontal lateralization on total spectrum amplitude power and right occipital lateralization in Delta activity during waking. In contrast, during REM sleep, right frontal lateralization in Theta and Beta activities and right lateralization in occipital Delta activity was observed. These results suggest that spontaneous EEG activities generated during waking and REM sleep are supported in part by a common thalamo-cortical neural network (right occipital Delta dominance) while additional, possibly neuro-cognitive factors modulate waking left prefrontal dominance and REM sleep right frontal dominance.     

睡眠对恐惧学习的影响及其认知神经机制

睡眠问题可能会诱发恐惧相关情绪障碍(焦虑、创伤性应激障碍、恐怖症等),研究睡眠影响恐惧学习的认知神经机制,有助于增强对恐惧相关情绪障碍的预测、诊断和治疗。以往研究表明睡眠剥夺影响恐惧习得和消退主要是通过抑制vmPFC活动,阻碍其与杏仁核的功能连接,从而导致恐惧习得增强或是消退学习受损。进一步研究发现睡眠不同阶段对恐惧学习相关脑区有独特的影响:剥夺(缺乏)快速眼动睡眠会抑制vmPFC活动、增强杏仁核、海马激活,导致恐惧习得增强,消退学习受损,此外边缘皮层的功能连接减少破坏了记忆巩固(恐惧记忆和消退记忆);而慢波睡眠主要与海马变化有关,慢波睡眠期间进行目标记忆重激活可促进恐惧消退学习。未来研究需要增加睡眠影响恐惧泛化的神经机制研究、及昼夜节律中断对恐惧消退的影响,以及关注动物睡眠研究向人类睡眠研究转化中存在的问题。     

Testing the involvement of the prefrontal cortex in lucid dreaming: A tDCS study

Recent studies suggest that lucid dreaming (awareness of dreaming while dreaming) might be associated with increased brain activity over frontal regions during rapid eye movement (REM) sleep. By applying transcranial direct current stimulation (tDCS), we aimed to manipulate the activation of the dorsolateral prefrontal cortex (DLPFC) during REM sleep to increase dream lucidity. Nineteen participants spent three consecutive nights in a sleep laboratory. On the second and third nights they randomly received either 1 mA tDCS for 10 min or sham stimulation during each REM period starting with the second one. According to the participants’ self-ratings, tDCS over the DLPFC during REM sleep increased lucidity in dreams. The effects, however, were not strong and found only in frequent lucid dreamers. While this indicates some preliminary support for the involvement of the DLPFC in lucid dreaming, further research, controlling for indirect effects of stimulation and including other brain regions, is needed.     

Cognitive and emotional processes during dreaming: a neuroimaging view

Dream is a state of consciousness characterized by internally-generated sensory, cognitive and emotional experiences occurring during sleep. Dream reports tend to be particularly abundant, with complex, emotional, and perceptually vivid experiences after awakenings from rapid eye movement (REM) sleep. This is why our current knowledge of the cerebral correlates of dreaming, mainly derives from studies of REM sleep. Neuroimaging results show that REM sleep is characterized by a specific pattern of regional brain activity. We demonstrate that this heterogeneous distribution of brain activity during sleep explains many typical features in dreams. Reciprocally, specific dream characteristics suggest the activation of selective brain regions during sleep. Such an integration of neuroimaging data of human sleep, mental imagery, and the content of dreams is critical for current models of dreaming; it also provides neurobiological support for an implication of sleep and dreaming in some important functions such as emotional regulation.     

Sleep imaging and the neuro-psychological assessment of dreams

Recent neuroimaging studies show that human rapid-eye-movement (REM) sleep is characterized by a specific pattern of regional brain activity. Although this is usually interpreted in relation to physiological and cellular mechanisms, the specific regional distribution of brain activity during REM sleep might also be linked to specific dream features. Remarkably, several bizarre features of normal dreams have similarities with well-known neuropsychological syndromes after brain damage, such as delusional misidentifications for faces and places. We propose that neuropsychological analysis of dream content might offer new ways of interpreting neuroimaging maps of sleep, and make specific predictions for future neuroimaging studies.     

Interhemispheric EEG coherence during sleep and wakefulness in left- and right-handed subjects

REM sleep is associated with the production of complex imagery sequences. Yet research is divided as to whether different brain regions are more or less coordinated in their functioning at this time. Some research suggests that there may occur a functional disconnection of the left and right cerebral hemispheres during REM sleep which is similar to the disconnection syndrome seen after corpus callosotomy. Other research suggests that an increase in interhemispheric coordination occurs. On the assumption that hemispheric coordination is reflected in the EEG coherence measure, we explored differences in interhemispheric coherence recorded in six left- and six right-handed normal subjects during periods of wakefulness, stage REM, stage 2, and stage 3/4 sleep. Strong evidence was found that mean EEG coherence values are larger during sleep than during waking and that they are approximately equal for the different stages of sleep. Frontal electrode placements demonstrated a slightly different pattern of coherence than central, parietal, or occipital placements. Furthermore, coherence values were larger for left-handed subjects over the occipital region during wakefulness, stage 2, and stage REM sleep, but not during stage 3/4 sleep. Coherence was not different for male and female subjects. These findings oppose the interpretation that a functional disconnection of hemispheres occurs during REM sleep and favor the interpretation that sleep in general is a state of heightened cortical coordination. Moreover, greater interhemispheric coherence over occipital brain regions in left-handed subjects suggests possible differences in the cognitive processes of these subjects during waking and dreaming states.     

Dreaming without REM sleep

To test whether mental activities collected from non-REM sleep are influenced by REM sleep, we suppressed REM sleep using clomipramine 50mg (an antidepressant) or placebo in the evening, in a double blind cross-over design, in 11 healthy young men. Subjects were awakened every hour and asked about their mental activity. The marked (81%, range 39-98%) REM-sleep suppression induced by clomipramine did not substantially affect any aspects of dream recall (report length, complexity, bizarreness, pleasantness and self-perception of dream or thought-like mentation). Since long, complex and bizarre dreams persist even after suppressing REM sleep either partially or totally, it suggests that the generation of mental activity during sleep is independent of sleep stage.     

Mental time travel to the future might be reduced in sleep

We present a quantitative study of mental time travel to the future in sleep. Three independent, blind judges analysed a total of 563 physiology-monitored mentation reports from sleep onset, REM sleep, non-REM sleep, and waking. The linguistic tool for the mentation report analysis is based on established grammatical and cognitive-semantic theories and has been validated in previous studies. Our data indicate that REM and non-REM sleep must be characterized by a reduction in mental time travel to the future, which would support earlier physiological evidence at the level of brain function.     

The prefrontal cortex in sleep

Experimental data indicate a role for the prefrontal cortex in mediating normal sleep physiology, dreaming and sleep-deprivation phenomena. During nonrandom-eye-movement (NREM) sleep, frontal cortical activity is characterized by the highest voltage and the slowest brain waves compared to other cortical regions. The differences between the self-awareness experienced in waking and its diminution in dreaming can be explained by deactivation of the dorsolateral prefrontal cortex during REM sleep. Here, we propose that this deactivation results from a direct inhibition of the dorsolateral prefrontal cortical neurons by acetylcholine, the release of which is enhanced during REM sleep. Sleep deprivation influences frontal executive functions in particular, which further emphasizes the sensitivity of the prefrontal cortex to sleep.     

Electroencephalographic and autonomic alterations in subjects with frequent nightmares during pre-and post-REM periods

Abnormal arousal processes, sympathetic influences, as well as wake-like alpha activity during sleep were reported as pathophysiological features of Nightmare Disorder. We hypothesized that in Nightmare Disorder, wake-like cortical activity and peripheral measures linked to arousals would be triggered by physiological processes related to the initiation of REM periods. Therefore, we examined electroencephalographic (EEG), motor and autonomous (cardiac) activity in a group of nightmare (NM) and healthy control (CTL) subjects during sleep-state-transitions while controlling for the confounding effects of trait anxiety. Based on the second-nights’ polysomnographic recordings of 19 Nightmare Disordered (NM) and 21 control (CTL) subjects, we examined the absolute power spectra focusing on the alpha range, measures of heart rate variability (HRV) and motor (muscle tone) activity during pre-REM and post-REM periods, separately. According to our results, the NM group exhibited increased alpha power during pre-REM, but not in post-REM, or stable, non-transitory periods. While CTL subjects showed increased HRV during pre-REM periods in contrast to post-REM ones, NM subjects did not exhibit such sleep state-specific differences in HRV, but showed more stable values across the examined sleep stages and less overall variability reflecting generally attenuated parasympathetic activity during sleep-state-transitions and during stable, non-transitory NREM states. These differences were not mediated by waking levels of trait anxiety. Moreover, in both groups, significant differences emerged regarding cortical and motor (muscle tone) activity between pre-REM and post-REM conditions, reflecting the heterogeneity of NREM sleep. Our findings indicate that NM subjects’ sleep is compromised during NREM–REM transitions, but relatively stabilized after REM periods. The coexistence of sleep-like and wake-like cortical activity in NM subjects seems to be triggered by REM/WAKE promoting neural activity. We propose that increased arousal-related phenomena in NREM–REM transitions might reflect altered emotional processing in NM subjects.     

REM mentation in narcoleptics and normals: an empirical test of two neurocognitive theories

This study tested the two main neurocognitive models of dreaming by using cognitive data elicited from REM sleep in normals and narcoleptics. The two models were the "activation-only" view which holds that, in the context of sleep, overall activation of the brain is sufficient for consciousness to proceed in the manner of dreaming (e.g., Antrobus, 1991; Foulkes, 1993; Vogel, 1978); and the Activation, Input source, Modulation (AIM model), which predicts that not only brain activation level but also neurochemical modulatory systems exert widespread effects upon dreaming (Hobson & McCarley, 1977; Hobson, Pace-Schott, & Stickgold, 2000). Mental activity was studied in nocturnal REM in 15 narcoleptics and 9 normal healthy persons and in REM at the onset of daytime naps and nighttime sleep (SOREM) in narcoleptics. The study was performed in the subjects' homes, using instrumental awakenings and ambulatory polysomnographic techniques, and focused upon visual vividness, mentation report length, improbable and discontinuous bizarre features, and reflective consciousness. Within each subject group, most cognitive variables tended to fluctuate in line with expected variations in circadian activation level. When comparing the cognitive variables between the two groups, reflective consciousness was clearly highest in narcoleptics, whereas improbabilities and discontinuities were lower, with mentation report length and visual vividness differing less between the groups. These findings are consistent with the AIM model of sleep mentation, but not with the activation-only model.     

William James''s The Fringe of Consciousness REM Mentation in Narcoleptics and Normals: Reply to Tore Nielsen

This study tested the two main neurocognitive models of dreaming by using cognitive data elicited from REM sleep in normals and narcoleptics. The two models were the "activation-only" view which holds that, in the context of sleep, overall activation of the brain is sufficient for consciousness to proceed in the manner of dreaming (e.g., Antrobus, 1991; Foulkes, 1993; Vogel, 1978); and the Activation, Input source, Modulation (AIM model), which predicts that not only brain activation level but also neurochemical modulatory systems exert widespread effects upon dreaming (Hobson & McCarley, 1977; Hobson, Pace-Schott, & Stickgold, 2000). Mental activity was studied in nocturnal REM in 15 narcoleptics and 9 normal healthy persons and in REM at the onset of daytime naps and nighttime sleep (SOREM) in narcoleptics. The study was performed in the subjects' homes, using instrumental awakenings and ambulatory polysomnographic techniques, and focused upon visual vividness, mentation report length, improbable and discontinuous bizarre features, and reflective consciousness. Within each subject group, most cognitive variables tended to fluctuate in line with expected variations in circadian activation level. When comparing the cognitive variables between the two groups, reflective consciousness was clearly highest in narcoleptics, whereas improbabilities and discontinuities were lower, with mentation report length and visual vividness differing less between the groups. These findings are consistent with the AIM model of sleep mentation, but not with the activation-only model.     

Brain-mind states: reciprocal variation in thoughts and hallucinations

The exclusion of thinking from recent studies of sleep mentation has hindered a full appreciation of how cognitive activity differs across the states of waking and sleep. To overcome this limitation, this study investigated thoughts and hallucinations using experience sampling, home-based sleep-wake monitoring, and formal analyses of the psychological data. The prevalence of thoughts decreased gradually from waking through sleep onset and non-REM sleep, to reach its nadir in REM sleep, whereas hallucinations increased sharply across these states. Furthermore, multiple occurrences of hallucinations but not of thoughts increased significantly from sleep onset through non-REM sleep, to a peak in REM sleep. This reciprocity in thoughts and hallucinations might reflect a progressive shift from high to low aminergic-to-cholinergic neuromodulatory ratios across wake-sleep states, accompanied by an array of changes in the regional activation patterns of the brain.     

A review of mentation in REM and NREM sleep: "covert" REM sleep as a possible reconciliation of two opposing models

Numerous studies have replicated the finding of mentation in both rapid eye movement (REM) and nonrapid eye movement (NREM) sleep. However, two different theoretical models have been proposed to account for this finding: (1) a one-generator model, in which mentation is generated by a single set of processes regardless of physiological differences between REM and NREM sleep; and (2) a two-generator model, in which qualitatively different generators produce cognitive activity in the two states. First, research is reviewed demonstrating conclusively that mentation can occur in NREM sleep; global estimates show an average mentation recall rate of about 50% from NREM sleep--a value that has increased substantially over the years. Second, nine different types of research on REM and NREM cognitive activity are examined for evidence supporting or refuting the two models. The evidence largely, but not completely, favors the two-generator model. Finally, in a preliminary attempt to reconcile the two models, an alternative model is proposed that assumes the existence of covert REM sleep processes during NREM sleep. Such covert activity may be responsible for much of the dreamlike cognitive activity occurring in NREM sleep.     

Relation between polysomnographic measures during nocturnal sleep and a quotient of behavioral development in infants with developmental disabilities

Polysomnographic features during nocturnal sleep were investigated in 27 infants with developmental disabilities. With the use of a multiple regression analysis, 78% of the variance of a Development Quotient (DQ) measured by a questionnaire on behavioral development for infants was explained by sleep measures. Of 14 sleep measures employed in the study, (1) cumulative awakening time during a nocturnal sleep time, (2) duration of REM stage, and (3) percentage of REM to total sleep time were important in association with the DQ. The findings are consistent with the sleep-cognition hypothesis proposed by Espie, et al.     

Brain Gene Expression During REM Sleep Depends on Prior Waking Experience

In most mammalian species studied, two distinct and successive phases of sleep, slow wave (SW), and rapid eye movement (REM), can be recognized on the basis of their EEG profiles and associated behaviors. Both phases have been implicated in the offline sensorimotor processing of daytime events, but the molecular mechanisms remain elusive. We studied brain expression of the plasticity-associated immediate-early gene (IEG) zif-268 during SW and REM sleep in rats exposed to rich sensorimotor experience in the preceding waking period. Whereas nonexposed controls show generalized zif-268 down-regulation during SW and REM sleep, zif-268 is upregulated during REM sleep in the cerebral cortex and the hippocampus of exposed animals. We suggest that this phenomenon represents a window of increased neuronal plasticity during REM sleep that follows enriched waking experience.     

Cerebral blood flow in normal and abnormal sleep and dreaming

Measurements of regional or local cerebral blood flow (CBF) by the xenon-133 inhalation method and stable xenon computerized tomography CBF (CTCBF) method were made during relaxed wakefulness and different stages of REM and non-REM sleep in normal age-matched volunteers, narcoleptics, and sleep apneics. In the awake state, CBF values were reduced in both narcoleptics and sleep apneics in the brainstem and cerebellar regions. During sleep onset, whether REM or stage I-II, CBF values were paradoxically increased in narcoleptics but decreased severely in sleep apneics, while in normal volunteers they became diffusely but more moderately decreased. In REM sleep and dreaming CBF values greatly increased, particularly in right temporo-parietal regions in subjects experiencing both visual and auditory dreaming.     

Dreaming,cognition, and physical illness: Part I

Part I of a two part article on the effect upon dreaming on physical illness briefly explores the historical medico-philosophical antecedents of the notion that dreams can be diagnostic of bodily disease. Modern sleep research findings relating REM sleep to physiologic changes are also explored. The controversy of whether dreams are merely the consequence of random brain activity or whether they are a valid psychological phenomenon is discussed. Six contemporary views of the function of REM sleep are outlined. A seventh view of dreaming, that of a “cognitive monitoring system” is suggested. Like earlier historical notions, it is suggested that dreaming is a cognitive activity that processes bodily cues indicating illness or disease. Part II. presents a clinical compendium of dreams relating to Part I.