Functional microstates within human REM sleep: first evidence from fMRI of a thalamocortical network specific for phasic REM periods

High thalamocortical neuronal activity characterizes both, wakefulness and rapid eye movement (REM) sleep, but apparently this network fulfills other roles than processing external information during REM sleep. To investigate thalamic and cortical reactivity during human REM sleep, we used functional magnetic resonance imaging with simultaneous polysomnographic recordings while applying acoustic stimulation. Our observations indicate two distinct functional substates within general REM sleep. Acoustic stimulation elicited a residual activation of the auditory cortex during tonic REM sleep background without rapid eye movements. By contrast, periods containing bursts of phasic activity such as rapid eye movements appear characterized by a lack of reactivity to sensory stimuli. We report a thalamocortical network including limbic and parahippocampal areas specifically active during phasic REM periods. Thus, REM sleep has to be subdivided into tonic REM sleep with residual alertness, and phasic REM sleep with the brain acting as a functionally isolated and closed intrinsic loop.     

On the origin of early REM episodes in the sleep of depressed patients: a comparison of three hypotheses

Shortened latency of rapid eye movement (REM) sleep is a feature frequently observed in depressed patients. Three hypotheses on the origin of early REM sleep episodes propose that short REM latency is due to (1) a phase-shift of one subset of the circadian rhythms relative to other circadian rhythms, (2) a loss of inhibition of REM sleep due to a slow wave sleep deficit, or (3) a reduction in amplitude of a putative circadian arousal cycle. From an analysis of experimental data, it is concluded that the hypothesis of a reduced circadian amplitude best explains the early occurrence of REM sleep.     

Seizure susceptibility decreases with enhancement of rapid eye movement sleep

The study examined the effect of enhanced rapid eye movement (REM) sleep duration on the seizure threshold determined by electrical stimulation of the amygdala in rats. The duration of REM sleep was specifically increased by the microinjection of a cholinergic agonist, carbachol, into the pontine reticular formation. This was accompanied by a significant increase in the threshold current required to elicit an afterdischarge in the amygdala. The results suggest that an increase in REM sleep decreases the likelihood of cortical seizure activity, an effect that is manifest even in other stages of the sleep-wakefulness cycle and not only in the REM state, per se.     

REM-sleep related hypermotor seizures: Video documentation and ictal source imaging

IntroductionRapid eye movement (REM) sleep has an inhibitory effect on epileptiform EEG discharges, and seizures occur extremely rarely in REM sleep.Case studyWe present the case and video recordings of a 10-year-old boy, with sleep-related hypermotor seizures starting from REM sleep, identified from videoEEG recordings. The semiology comprised intense fear, tachycardia, tachypnea, followed by hypermotor manifestations. Further investigations included brain MRI and source localization of the EEG signals. Multiple antiepileptic drugs were tried, the patient obtaining a good control of the seizures in the last 2.5 years with eslicarbazepine.Discussion and conclusionThe ictal EEG source imaging showed seizure onset in the anterior part of the right insula, with propagation to the orbitofrontal area, confirmed by the semiological sequence. Although rare, focal seizures can be triggered by REM sleep and our findings suggest that deficient maturation of brain areas involved in sleep modulation might induce insufficient desynchronization during REM sleep, thus allowing seizure emergence.     

Rem sleep in depressed patients: Different attempts to achieve adaptation

Twenty-seven depressed patients and 10 healthy subjects were investigated in the sleep laboratory during two to three consecutive nights. Eleven of the 27 patients demonstrated the “first night effect” (group I) and 11 other patients demonstrated a clear absence of the “first night effect” (group II). Five of the 27 depressed patients were omitted from the study because they did not fit criteria for first night effect. The 10 healthy controls demonstrated a first night effect. In group I, the duration of the first rapid eye movement (REM) sleep episode was increased on the first night and on the second night the REM sleep latency was decreased, whereas REM sleep duration and eye movement (EM) density was increased. The number of the short sleep cycles (less than 40 minutes) was greater in group I versus group II and the percentage of slow-wave sleep (SWS) was also higher in group I. In depressed patients with the “first night effect” the enhanced REM sleep requirement is satisfied not only by an increased REM sleep duration but also by the improved REM sleep quality that is crucial for adaptation. The adaptive role of the increased first REM period and the increased EM density in this period is very limited.     

On the explanation of short REM latencies in depression

Sleep in depression is characterized by the occurrence of episodes of rapid eye movement (REM) sleep at sleep onset. The empirical foundations of three hypotheses about the origin of this phenomenon are examined: A circadian rhythm hypothesis stating that sleep onset REM episodes (SOREMs) are the result of an abnormal phase-position of the REM sleep production cycle. A REM sleep-slow wave sleep interaction hypothesis that attributes SOREMs to a low non-REM sleep propensity. A circadian amplitude hypothesis, in which a flattening of the circadian arousal cycle is thought to be causally related to SOREMs. None of the hypotheses are found to be supported by firm empirical evidence.     

Further evidences for sleep instability and impaired spindle-delta dynamics in schizophrenia: a whole-night polysomnography study with neuroloop-gain and sleep-cycle analysis

ObjectiveSleep offers a unique window into the brain dysfunctions in schizophrenia. Many past sleep studies have reported abnormalities in both macro-sleep architecture (like increased awakenings) as well as micro-sleep-architecture (like spindle deficits) in patients with schizophrenia (PSZ). The present study attempts to replicate previous reports of macro- and micro-sleep-architectural abnormalities in schizophrenia. In addition, the study also examined sleep-stage changes and spindle-delta dynamics across sleep-cycles to provide further evidence in support of the dysfunctional thalamocortical mechanisms causing sleep instability and poor sleep maintenance associated with schizophrenia pathophysiology.MethodsWhole-night polysomnography was carried out among 45 PSZ and 39 age- and gender-matched healthy control subjects. Sleep-stage dynamics were assessed across sleep-cycles using a customized software algorithm. Spindle-delta dynamics across sleep-cycles were determined using neuroloop-gain analysis.ResultsPSZ showed macro-sleep architecture abnormalities such as prolonged sleeplessness, increased intermittent-awakenings, long sleep-onset latency, reduced non-rapid eye movement (NREM) stage 2 sleep, increased stage transitions, and poor sleep efficiency. They also showed reduced spindle density (sigma neuroloop-gain) but comparable slow wave density (delta neuroloop-gain) throughout the sleep. Sleep-cycle-wise analysis revealed transient features of sleep instability due to significantly increased intermittent awakenings especially in the first and third sleep-cycles, and unstable and recurrent stage transitions in both NREM (first sleep-cycle) and rapid eye movement (REM) sleep-periods (second sleep-cycle). Spindle deficits were persistent across the first three cycles and were positively correlated with sleep disruption during the subsequent REM sleep.ConclusionsIn addition to replicating previously reported sleep deficits in PSZ, the current study showed subtle deficits in NREM–REM alterations across whole-night polysomnography. These results point towards a possible maladaptive interplay between unstable thalamocortical networks, resulting in sleep-cycle-specific instability patterns associated with schizophrenia pathophysiology.     

Increased REM eye movement density in self-rated depression

Zung depression scores were positively related to eye movement density in a sample of 19 noncomplaining young adult males. The subjects were not clinically depressed and had average scores on the Depression Scale of the Minnesota Multiphasic Personality Inventory. There was no relation of Zung depression to rapid eye movement (REM) latency, stage 3 and stage 4 sleep, or REM in the first third of the sleep period. The finding is consistent with the hypothesis of a disinhibition or phase lead of REM sleep phasic events in depression.     

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.     

Arousals in nocturnal groaning

Background and objectiveNocturnal groaning (catathrenia) is a chronic sleep disorder classified as parasomnia with unclear effects on sleep and life quality. It is characterized by repeated episodes of monotonous vocalization in prolonged expiration (episodes of bradypnea) occurring mostly in REM sleep. We sought to assess its impact on sleep microstructure, i.e., the frequency of arousals relative to the groaning episodes. The frequency, duration and sleep-stage distribution of the groaning episodes were also studied.MethodsEight patients with nocturnal groaning (5 male, 3 female, age range 11–32 years, mean age 23 ± 7.1) were evaluated. All underwent standard neurologic examination and nocturnal videopolysomnography for two consecutive nights. The second night polysomnography data were used to evaluate sleep parameters. The groaning episodes (bradypneic events) were counted separately, not as clusters.ResultsSleep macrostructure revealed no specific changes. The number of groaning episodes/bradypneic events during the night varied from 40 to 182 (total number 725). The duration of bradypnea was from 2 to 46 s (mean duration 12.5 s). Groaning episodes prevailed in REM sleep (76.5%). The rate for NREM 2 was 21.5%, and only sporadic episodes were noted in delta sleep (1.9%); 63.3% of the events were associated with arousals, and in 94% of them an arousal occurred before or together with the onset of bradypnea. The arousal index was increased in 5 patients (mean 20.4). Bruxism was present in 4 cases, in 1 patient appearing in close association with groaning episodes. Ronchopathy was noted in 4 cases.ConclusionAlmost two-thirds of the groaning episodes were connected with arousals. Hypothetically, nocturnal groaning may well be a source of sleep disruption (mainly REM) in some cases. Because an arousal mostly preceded or coincided with groaning we believe that arousal mechanisms may be involved in the pathogenesis of nocturnal groaning.     

Activation of visual cortex in REM sleep measured by 24-channel NIRS imaging.

To visualize dreaming brain functions we studied hemodynamic changes in the visual cortex during the transition from non-rapid eye movement (NREM) to rapid eye movement (REM) sleep, using a 24-channel Near-Infrared Spectroscopy (NIRS) imaging method. Results were compared to the activation in visual cortex by visual stimulation during wakefulness. Subjects were four healthy males between 25 and 49 years of age. Five all-night polysomnographic and NIRS recordings were made. Increases in the oxygenated hemoglobin concentration in visual cortex were observed from nine of 14 REM periods. The activated areas were broader during REM sleep than during visual stimulation. These findings suggest that activation of visual cortex in REM sleep might represent dream-related brain activity.     

Effects of trazodone hydrochloride and imipramine on polysomnography in healthy subjects

Polysomnography was performed on eight healthy men with trazodone hydrochloride, imipramine and placebo. Trazodone hydrochloride increased slow wave sleep significantly. Imipramine prolonged rapid eye movement (REM) latency and decreased the percentage of REM sleep significantly. Trazodone decreased stages 1 and 2 sleep, while imipramine increased it. These findings suggest that the antidepressive effect of trazodone might be different from that of imipramine with the suppression of REM sleep.     

Rapid eye movement density shows trends across REM periods but is uncorrelated with NREM delta in young and elderly human subjects

Saccade-like eye movements are the most prominent phasic component of rapid eye movement (REM) sleep. Eye movement density (EMD) appears to be negatively related to sleep depth. Thus, EMD is depressed by sleep deprivation. We sought to determine in 19 young normal (YN) and 19 elderly normal (EN) subjects: (a) whether EMD is correlated with delta EEG in baseline sleep; (b) whether EMD is increased by daytime naps; and (c) whether EMD patterns across sleep cycles differ in the two age groups. Subjects participated in four separate 2-day recording sessions, each consisting of a baseline night, a daytime nap, and post nap night. EMD was measured as 0.3-2 Hz integrated amplitude (IA)/20 s stage REM. EMD was not correlated with rate of non rapid eye movement (NREM) delta production (power/min) in the baseline sleep of either group. Changes in EMD and delta power/min on post nap nights also were uncorrelated. These data indicate that very strong changes in sleep depth (state) are required to overcome the individual stability (traits) of NREM delta and eye movement density. ANOVA for EMD across REM periods 1-4 showed a significant cycle effect and a significant age x cycle interaction. These effects were mainly due to YNs having depressed EMD in the first REM period, likely due to the low arousal level early in sleep in these subjects. Compared with waking saccades the saccade eye movements of REM sleep have received little investigation. Further study of these movements could shed new light on neurophysiology of REM sleep. Such studies might also be clinically useful because the density of these movements appears to be related to depression and (independently) to cognitive function in individuals with brain impairment.     

A life-sustaining function for REM sleep: A theory

A hypothesis has been advanced that the primary function of rapid eye movement (REM) sleep is to provide periodic endogenous stimulation to the brain which serves to maintain minimum requisite levels of CNS activity throughout sleep. REM, in effect, is the mechanism used by the brain to promote and ensure recovery from sleep. Failures of REM may hinder, or in extreme cases, prevent arousal from sleep. The possibility that two fatal sleep-associated syndromes (Sudden Infant Death Syndrome and the Oriental Nocturnal Death Syndrome) may involve deficits of REM was discussed.     

Cholinergic REM sleep induction response correlation with endogenous major depressive subtype

We compared central cholinergic responsiveness (using the latency to induction of rapid eye movement sleep after arecoline challenge as a response marker) in 90 subjects: patients with major depressive disorder (MDD) (n = 53), nonaffective psychiatric controls (n = 17), and normal controls (n = 20). MDD patients as a whole showed a supersensitive cholinergic response compared to nonaffective patients and normal subjects. Further analysis indicated a strong association between cholinergic supersensitivity and endogenous subtype of MDD, including a significant correlation with specific endogenous features such as distinct quality of mood, anhedonia, lack of reactivity, and agitation. Unlike rapid eye movement (REM) latency (a more conventional physiological marker), cholinergic sensitivity did not correlate with age or severity of illness but only with the presence of endogenous features. Previously described sleep physiological correlates such as REM latency and REM density of the first REM period also distinguished between endogenous and nonendogenous MDD. There was a statistically significant correlation between REM latency and arecoline REM induction response.     

Temporal coupling of rapid eye movements and cerebral activities during REM sleep

ObjectivesWe investigated event-related potentials time locked to the onset and offset of rapid eye movements during rapid eye movement (REM) sleep.MethodNine healthy university students participated in this study. Data were collected in a sleep laboratory. Rapid eye movements during REM sleep were recorded during natural nocturnal sleep. Saccades during wakefulness were recorded during a visually triggered task. Event-related potentials were averaged, time-locked to the onset and offset of eye movements.ResultsDuring REM sleep, a lambda-like response occurred over the occipital region, time-locked to the offset of rapid eye movements (similar to what occurs during wakefulness). Moreover, we found that a positive potential (P200r) occurred at about 200 ms, with the maximal amplitude over the central region and time-locked to the onset of rapid eye movements during REM sleep; this potential was not observed during wakefulness.ConclusionsDuring REM sleep, the P200r occurs with the start of rapid eye movements, and then the lambda-like response occurs after termination of the movements.SignificanceWe demonstrated temporal coupling of rapid eye movements and cerebral activities during REM sleep. These activities might provide a useful basis for future investigations of brain functions during REM sleep.     

A Discrete Glycinergic Neuronal Population in the Ventromedial Medulla That Induces Muscle Atonia during REM Sleep and Cataplexy in Mice

During rapid eye movement (REM) sleep, anti-gravity muscle tone and bodily movements are mostly absent, because somatic motoneurons are inhibited by descending inhibitory pathways. Recent studies showed that glycine/GABA neurons in the ventromedial medulla (VMM; Gly^VMM neurons) play an important role in generating muscle atonia during REM sleep (REM-atonia). However, how these REM-atonia-inducing neurons interconnect with other neuronal populations has been unknown. In the present study, we first identified a specific subpopulation of Gly^VMM neurons that play an important role in induction of REM-atonia by virus vector-mediated tracing in male mice in which glycinergic neurons expressed Cre recombinase. We found these neurons receive direct synaptic input from neurons in several brain stem regions, including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD; Glu^SLD neurons). Silencing this circuit by specifically expressing tetanus toxin light chain (TeTNLC) resulted in REM sleep without atonia. This manipulation also caused a marked decrease in time spent in cataplexy-like episodes (CLEs) when applied to narcoleptic orexin-ataxin-3 mice. We also showed that Gly^VMM neurons play an important role in maintenance of sleep. This present study identified a population of glycinergic neurons in the VMM that are commonly involved in REM-atonia and cataplexy.SIGNIFICANCE STATEMENT We identified a population of glycinergic neurons in the ventral medulla that plays an important role in inducing muscle atonia during rapid eye movement (REM) sleep. It sends axonal projections almost exclusively to motoneurons in the spinal cord and brain stem except to those that innervate extraocular muscles, while other glycinergic neurons in the same region also send projections to other regions including monoaminergic nuclei. Furthermore, these neurons receive direct inputs from several brainstem regions including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD). Genetic silencing of this pathway resulted in REM sleep without atonia and a decrease of cataplexy when applied to narcoleptic mice. This work identified a neural population involved in generating muscle atonia during REM sleep and cataplexy.     

Changes in REM sleep occurrence due to rhythmical auditory stimulation in the rat

The effects of the rhythmical delivery of an auditory stimulus (1000 Hz, from 50 to 100 dB, 20 ms, every 20 s) on the pattern of rapid eye movement (REM) sleep occurrence was studied in the rat. The stimulation was simultaneously carried out on pairs of rats over 5 consecutive days (10-h recording sessions), during which a tone of increasing intensity (50, 63, 75, 88, 100 dB) was used. In each experimental session, auditory stimulation was triggered by the REM sleep occurrence of one rat (REMS-selective stimulation) whilst the other rat simultaneously received the same stimuli, but during any stage of the wake-sleep cycle (REMS-unselective stimulation). The results showed that the total amount of REM sleep in the 10-h recording session was increased over the 5 days of stimulation in the REMS-unselective group. This effect was due to an increase in the mean duration of REM sleep episodes. However, no significant changes were observed in animals under REMS-selective stimulation, nor in a third group of animals in which the spontaneous evolution of REM sleep occurrence (REMS-spontaneous) was studied. Since 86% of the stimuli under the REMS-unselective auditory stimulation fell outside REM sleep, the result would suggest that REM sleep occurrence is affected when the stimuli are delivered during a time period (i.e. during wakefulness or non-REM sleep) in which it is well known that physiological regulations are fully operant.     

Spontaneous nystagmus across the sleep-wake cyc̀le in vegetative state patients

The presence of spontaneous CNS nystagmus during wakefulness was documented for the first time in 6 vegetative-state (VS) patients. Nystagmus of smaller amplitude as compared to the awake state was consistently detected in each patient during stage 1 of sleep. There was complete absence of nystagmus during stage 2 and slow wave sleep (SWS) in all the patients. Clear nystagmus episodes were observed during rapid eye movement (REM) sleep in all patients. Some nystagmus episodes followed rapid eye movements (REMs), some were unrelated to REMs while others were superimposed on REMs. It is suggested that spontaneous neural activation during REM sleep may allow the episodic emergence of nystagmus during this sleep stage.     

Cell-Type-Specific Dynamics of Calcium Activity in Cortical Circuits over the Course of Slow-Wave Sleep and Rapid Eye Movement Sleep

Sleep shapes cortical network activity, fostering global homeostatic downregulation of excitability while maintaining or even upregulating excitability in selected networks in a manner that supports memory consolidation. Here, we used two-photon calcium imaging of cortical layer 2/3 neurons in sleeping male mice to examine how these seemingly opposing dynamics are balanced in cortical networks. During slow-wave sleep (SWS) episodes, mean calcium activity of excitatory pyramidal (Pyr) cells decreased. Simultaneously, however, variance in Pyr population calcium activity increased, contradicting the notion of a homogenous downregulation of network activity. Indeed, we identified a subpopulation of Pyr cells distinctly upregulating calcium activity during SWS, which were highly active during sleep spindles known to support mnemonic processing. Rapid eye movement (REM) episodes following SWS were associated with a general downregulation of Pyr cells, including the subpopulation of Pyr cells active during spindles, which persisted into following stages of sleep and wakefulness. Parvalbumin-positive inhibitory interneurons (PV-In) showed an increase in calcium activity during SWS episodes, while activity remained unchanged during REM sleep episodes. This supports the view that downregulation of Pyr calcium activity during SWS results from increased somatic inhibition via PV-In, whereas downregulation during REM sleep is achieved independently of such inhibitory activity. Overall, our findings show that SWS enables upregulation of select cortical circuits (likely those which were involved in mnemonic processing) through a spindle-related process, whereas REM sleep mediates general downregulation, possibly through synaptic re-normalization.SIGNIFICANCE STATEMENT Sleep is thought to globally downregulate cortical excitability and, concurrently, to upregulate synaptic connections in neuron ensembles with newly encoded memory, with upregulation representing a function of sleep spindles. Using in vivo two-photon calcium imaging in combination with surface EEG recordings, we classified cells based on their calcium activity during sleep spindles. Spindle-active pyramidal (Pyr) cells persistently increased calcium activity during slow-wave sleep (SWS) episodes while spindle-inactive cells decreased calcium activity. Subsequent rapid eye movement (REM) sleep episodes profoundly reduced calcium activity in both cell clusters. Results indicate that SWS allows for a spindle-related differential upregulation of ensembles whereas REM sleep functions to globally downregulate networks.