Tonic Rapid Eye Movement Research Articles

Heart rate variability and cordance in rapid eye movement sleep as biomarkers of depression and treatment response

ObjectivesThe relevance of rapid eye movement (REM) sleep in affective disorders originates from its well-known abnormalities in depressed patients, who display disinhibition of REM sleep reflected by increased frequency of rapid eye movements (REM density). In this study we examined whether heart rate variability (HRV) and prefrontal theta cordance, both derived from REM sleep, could represent biomarkers of antidepressant treatment response. MethodsIn an open-label, case-control design, thirty-three in-patients (21 females) with a depressive episode were treated with various antidepressants for four weeks. Response to treatment was defined as a ≥50% reduction of HAM-D score at the end of the fourth week. Sleep EEG was recorded after the first and the fourth week of medication. HRV was derived from 3-min artifact-free electrocardiogram segments during REM sleep. Cordance was computed for prefrontal EEG channels in the theta frequency band during tonic REM sleep. ResultsHRV during REM sleep was decreased in depressed patients at week four as compared to controls (high effect size; Cohen's d > 1), and showed a negative correlation with REM density in both, healthy subjects and patients at week four. Further, the fourteen responders had significantly higher prefrontal theta cordance as compared to the nineteen non-responders after the first week of antidepressant medication; in contrast, HRV at week one did not discriminate between responders and non-responders. ConclusionsOur data suggest that HRV in REM sleep categorizes healthy subjects and depressed patients, whereas REM sleep-derived prefrontal cordance may predict the response to antidepressant treatment in depressed patients.

Insomnia and somnolence in idiopathic RBD: a prospective cohort study

Although some sleep disorders are markers of prodromal Parkinson’s disease and dementia with Lewy bodies, it is unclear whether insomnia and somnolence can predict disease. We assessed a large cohort of patients with idiopathic rapid eye movement sleep behavior disorder and age/sex matched controls, comparing the Epworth sleepiness scale, the Insomnia Severity Index, the Pittsburgh Sleep Quality Index, and polysomnographic variables. In those with repeated scales, we assessed change over time. Finally, we assessed whether sleep abnormalities predicted defined neurodegenerative disease. The 151 patients (age = 65.9, 75% male) completed sleep scales and were included. Epworth scores were similar between patients and controls (7.0+/−4.6 vs. 7.2+/−4.7, p = 0.77), and did not progress with time (change = +0.46+/−2.1, p = 0.45). Epworth scores were similar between those who developed neurodegenerative disease and those remaining disease-free (6.7+/−4.4 vs. 7.1+/−4.7, p = 0.70). Pittsburgh Index scores were higher in patients than controls (7.2+/−3.8 vs. 4.9+/−3.4, p = 0.004), mainly driven by the sleep disturbance/medication components (reflecting rapid eye movement sleep behavior disorder symptoms/treatment). Baseline Pittsburgh scores did not predict conversion to neurodegeneration, although sleep duration increased over time in those converting to neurodegenerative disease (+0.88+/−1.32 h, p = 0.014). Insomnia index scores were higher in patients than controls (10.0+/−5.5 vs. 6.35+/−4.66, p < 0.001), but declined over time (−1.43+/−5.09, p = 0.029) particularly in those converting to neurodegenerative disease. Finally, on polysomnogram, those with increased tonic rapid eye movement had higher risk of developing defined neurodegenerative disease (HR = 1.88, p = 0.039). In summary, we found that somnolence and insomnia do not predict neurodegeneration in idiopathic rapid eye movement sleep behavior disorder. As neurodegeneration progresses through prodromal stages, patients may have increasing sleep drive and duration.

Activation of the motor cortex during phasic rapid eye movement sleep.

When dreaming during rapid eye movement (REM) sleep, we can perform complex motor behaviors while remaining motionless. How the motor cortex behaves during this state remains unknown. Here, using intracerebral electrodes sampling the human motor cortex in pharmacoresistant epileptic patients, we report a pattern of electroencephalographic activation during REM sleep similar to that observed during the performance of a voluntary movement during wakefulness. This pattern is present during phasic REM sleep but not during tonic REM sleep, the latter resembling relaxed wakefulness. This finding may help clarify certain phenomenological aspects observed in REM sleep behavior disorder. Ann Neurol 2016;79:326–330

The effects of galantamine and buspirone on sleep structure: Implications for understanding sleep abnormalities in major depression.

The serotonergic and cholinergic systems are jointly involved in regulating sleep, but this balance is theorized to be disturbed in depressed individuals. The goal of this study was to use biological probes in healthy participants, to model the serotonergic/cholinergic imbalance of depression and its associated abnormalities in sleep structure. We tested 20 healthy female participants 18-30 years of age on four non-consecutive nights. Participants were given galantamine (a cholinergic agent), buspirone (a serotonergic agonist), both drugs together, or placebo before sleeping. Buspirone suppressed tonic rapid eye movement (REM): There was a significant increase in REM latency (p < 0.001). Galantamine increased tonic REM sleep, leading to more time spent in REM (p < 0.001) and shorter REM latency (p < 0.01). Galantamine and buspirone given together were not significantly different from the placebo night by REM sleep measures, but disrupted sleep more than either drug alone. These findings are partially consistent with the cholinergic literature about sleep in depression, notably short REM latency, higher percentage of total sleep time spent in REM and increased sleep fragmentation. The prolonged REM latency and reduced percentage of REM with buspirone resembled the effect of selective serotonin reuptake inhibitor antidepressants on REM sleep.

Physiological mechanisms of upper airway hypotonia during REM sleep.

Rapid eye movement (REM)-induced hypotonia of the major upper airway dilating muscle (genioglossus) potentially contributes to the worsening of obstructive sleep apnea that occurs during this stage. No prior human single motor unit (SMU) study of genioglossus has examined this possibility to our knowledge. We hypothesized that genioglossus SMUs would reduce their activity during stable breathing in both tonic and phasic REM compared to stage N2 sleep. Further, we hypothesized that hypopneas occurring in REM would be associated with coincident reductions in genioglossus SMU activity. The activity of genioglossus SMUs was studied in (1) neighboring epochs of stage N2, and tonic and phasic REM; and (2) during hypopneas occurring in REM. Sleep laboratory. 29 subjects (38 ± 13 y) (17 male). Natural sleep, including REM sleep and REM hypopneas. Subjects slept overnight with genioglossus fine-wire intramuscular electrodes and full polysomnography. Forty-two SMUs firing during one or more of stage N2, tonic REM, or phasic REM were sorted. Twenty inspiratory phasic (IP), 17 inspiratory tonic (IT), and five expiratory tonic (ET) SMUs were characterized. Fewer units were active during phasic REM (23) compared to tonic REM (30) and stage N2 (33). During phasic REM sleep, genioglossus IP and IT SMUs discharged at slower rates and for shorter durations than during stage N2. For example, the SMU peak frequency during phasic REM 5.7 ± 6.6 Hz (mean ± standard deviation) was less than both tonic REM 12.3 ± 9.7 Hz and stage N2 16.1 ± 10.0 Hz (P < 0.001). The peak firing frequencies of IP/IT SMUs decreased from the last breath before to the first breath of a REM hypopnea (11.8 ± 10.9 Hz versus 5.7 ± 9.4 Hz; P = 0.001). Genioglossus single motor unit activity is significantly reduced in REM sleep, particularly phasic REM. Single motor unit activity decreases abruptly at the onset of REM hypopneas.

Enhanced synchronization of gamma activity between frontal lobes during REM sleep as a function of REM sleep deprivation in man

Studies have shown that synchrony or temporal coupling of gamma activity is involved in processing and integrating information in the brain. Comparing rapid eye movement (REM) sleep to waking and non-REM (NREM) sleep, interhemispheric temporal coupling is higher, but lower between the frontal and posterior association areas of the same hemisphere. However, the homeostatic response of REM sleep temporal coupling after selective REM sleep deprivation (REMD) has not been studied. This study proposed exploring the effect of one night of selective REMD on the temporal coupling of cortical gamma activity during recovery REM sleep. Two groups of healthy subjects were subjected to either REMD by awakening them at each REM sleep onset, or to NREM sleep interruptions. Subjects slept four consecutive nights in the laboratory: first for adaptation, second as baseline, third for sleep manipulation, and fourth for recovery. Interhemispheric and intrahemispheric EEG correlations were analyzed during tonic REM (no eye movements) for the first three REM sleep episodes during baseline sleep, and recovery sleep after one night of selective REMD. Temporal coupling between frontal lobes showed a significant homeostatic rebound that increased during recovery REM sleep relative to baseline and controls. Results showed a rebound in temporal coupling between the two frontal lobes after REM sleep deprivation, indicating that the enhanced gamma temporal coupling that occurs normally during REM sleep has functional consequences. results suggest that synchronized activity during REM sleep may play an important role in integrating and reprocessing information.

Sleep spindles, mobile phones, lucid dreaming and sleep in Parkinson's disease and autism spectrum disorders

Sleep spindles, mobile phones, lucid dreaming and sleep in Parkinson's disease and autism spectrum disorders

Distinct features of fast oscillations in phasic and tonic rapid eye movement sleep

Spatiotemporal activity patterns of neurones are organized by different types of coherent network oscillations. Frequency content and cross-frequency coupling of cortical oscillations are strongly state-dependent, indicating that different patterns of wakefulness or sleep, respectively, support different cognitive or mnestic processes. It is therefore crucial to analyse specific sleep patterns with respect to their oscillations, including interaction between fast and slow rhythms. Here we report the oscillation profile of phasic rapid eye movement (REM), a form of REM sleep which has been implicated in hippocampus-dependent memory processing. In all analysed frequency bands (theta, gamma and fast gamma, respectively) we find higher frequencies and higher power in phasic REM compared to tonic REM or wakefulness. Theta-phase coupling of fast oscillations, however, was highest in tonic REM, followed by phasic REM and wakefulness. Our data suggest different roles of phasic and tonic REM for information processing or memory formation during sleep.

Rapid eye movement sleep behavior disorder and risk of dementia in Parkinson's disease: A prospective study

One of the most devastating nonmotor manifestations of PD is dementia. There are few established predictors of dementia in PD. In numerous cross-sectional studies, patients with rapid eye movement (REM) sleep behavior disorder (RBD) have increased cognitive impairment on neuropsychological testing, but no prospective studies have assessed whether RBD can predict Parkinson's dementia. PD patients who were free of dementia were enrolled in a prospective follow-up of a previously published cross-sectional study. All patients had a polysomnogram at baseline. Over a mean 4-year follow-up, the incidence of dementia was assessed in those with or without RBD at baseline using regression analysis, adjusting for age, sex, disease duration, and follow-up duration. Of 61 eligible patients, 45 (74%) were assessed and 42 were included in a full analysis. Twenty-seven patients had baseline RBD, and 15 did not. Four years after the initial evaluation, 48% with RBD developed dementia, compared to 0% of those without (P-adjusted = 0.014). All 13 patients who developed dementia had mild cognitive impairment on baseline examination. Baseline REM sleep atonia loss predicted development of dementia (% tonic REM = 73.2 ± 26.7 with dementia, 40.8 ± 34.5 without; P = 0.029). RBD at baseline also predicted the new development of hallucinations and cognitive fluctuations. In this prospective study, RBD was associated with increased risk of dementia. This indicates that RBD may be a marker of a relatively diffuse, complex subtype of PD.

Pointwise Transinformation Distinguishes a Recurrent Increase of Synchronization in the Rapid Eye Movement Sleep Electroencephalogram

The analysis of electroencephalogram (EEG) coupling patterns is essential for understanding how interrelations between cortical sites change with the wake-sleep cycle. Waking and sleep EEGs of 12 normal sleepers were analyzed by pointwise transinformation (PTI). Stage-dependent differences of PTI were assessed, and a spectral analysis of synchronized events was performed. A pattern of recurrent EEG synchronization was distinguished in all rapid eye movement (REM) sleep phases. The mean coupling of EEG leads differed regionally, with high coupling levels of frontal and occipital derivations and lower midtemporal and central coupling levels. Mean coupling levels were comparable in stages R, W, and N1 but were lower than in N2 and N3. An REM-specific pattern of low EEG synchronization was identified for F7-F8 and T3-T4, with lowest coupling levels during tonic REM sleep. Also, maximal intervals of uncoupled EEG were longer during tonic REM sleep. Because of these results, a new descriptive entity is proposed: the recurrent increase of synchronization in the EEG (RISE). This seems to reflect the dynamic aspects of spatiotemporal EEG synchronization on small time scales. A possibly specific low coupling pattern of the temporal leads may distinguish REM sleep from other states with a "desynchronized" EEG and, to some extent, tonic from phasic REM sleep.

Arousal thresholds during human tonic and phasic REM sleep

The goal of the present study was to investigate arousal thresholds (ATs) in tonic and phasic episodes of rapid eye movement (REM) sleep, and to compare the frequency spectrum of these sub-states of REM to non-REM (NREM) stages of sleep. We found the two REM stages to differ with regard to behavioural responses to external acoustic stimuli. The AT in tonic REM was indifferent from that in sleep stage 2, and ATs in phasic REM were similar to those in slow-wave sleep (stage 4). NREM and REM stages of similar behavioural thresholds were distinctly different with regard to their frequency pattern. These data provide further evidence that REM sleep should not be regarded a uniform state. Regarding electroencephalogram frequency spectra, we found that the two REM stages were more similar to each other than to NREM stages with similar responsivity. Ocular activity such as ponto-geniculo-occipital-like waves and microsaccades are discussed as likely modulators of behavioural responsiveness and cortical processing of auditory information in the two REM sub-states.

Highlights From The Literature

Highlights From The Literature

Cerebral sympathetic nerve activity has a major regulatory role in the cerebral circulation in REM sleep

Sympathetic nerve activity (SNA) in neurons projecting to skeletal muscle blood vessels increases during rapid-eye-movement (REM) sleep, substantially exceeding SNA of non-REM (NREM) sleep and quiet wakefulness (QW). Similar SNA increases to cerebral blood vessels may regulate the cerebral circulation in REM sleep, but this is unknown. We hypothesized that cerebral SNA increases during phasic REM sleep, constricting cerebral vessels as a protective mechanism against cerebral hyperperfusion during the large arterial pressure surges that characterize this sleep state. We tested this hypothesis using a newly developed model to continuously record SNA in the superior cervical ganglion (SCG) before, during, and after arterial pressure surges occurring during REM in spontaneously sleeping lambs. Arterial pressure (AP), intracranial pressure (ICP), cerebral blood flow (CBF), cerebral vascular resistance [CVR = (AP - ICP)/CBF], and SNA from the SCG were recorded in lambs (n = 5) undergoing spontaneous sleep-wake cycles. In REM sleep, CBF was greatest (REM > QW = NREM, P < 0.05) and CVR was least (REM < QW = NREM, P < 0.05). SNA in the SCG did not change from QW to NREM sleep but increased during tonic REM sleep, with a further increase during phasic REM sleep (phasic REM > tonic REM > QW = NREM, P < 0.05). Coherent averaging revealed that SNA increases preceded AP surges in phasic REM sleep by 12 s (P < 0.05). We report the first recordings of cerebral SNA during natural sleep-wake cycles. SNA increases markedly during tonic REM sleep, and further in phasic REM sleep. As SNA increases precede AP surges, they may serve to protect the brain against potentially damaging intravascular pressure changes or hyperperfusion in REM sleep.

The Influence of Obstructive Sleep Apnea and Gender on Genioglossus Activity During Rapid Eye Movement Sleep

The mechanisms contributing to worsening of obstructive sleep apnea (OSA) during rapid eye movement (REM) sleep have been minimally studied. Reduced upper-airway muscle tone may be an important contributor. Because respiratory events and the associated blood gas changes can influence genioglossus (GG) activity, we compared GG activity between OSA patients and control subjects during REM sleep using continuous positive airway pressure (CPAP) to minimize the influences of upper-airway resistance (RUA) and blood gas disturbances on GG activity. Twenty subjects (10 female subjects), 12 healthy individuals, and 8 OSA patients, were studied overnight. Sleep staging, epiglottic pressure, minute ventilation, and GG electromyogram (GGEMG) were recorded. GGEMG was compared between REM sleep with (phasic REM) and without (tonic REM) eye movements, non-REM (NREM) sleep, and wakefulness. Breathing frequency increased from stable NREM, to tonic REM to phasic REM sleep, whereas tidal volume and GGEMG decreased (ie, peak GGEMG: 3.0 +/- 0.7 vs 1.7 +/- 0.4 vs 1.2 +/- 0.3% max, respectively; p < 0.001). Reductions in GGEMG during REM sleep were not different between OSA patients and control subjects or between genders. When RUA and blood gas disturbances are minimized by CPAP, genioglossal activity is reduced in a stepwise manner from stable NREM, to tonic REM to phasic REM sleep to a similar extent in OSA and healthy individuals of both genders. Thus, an inherent abnormality in GG neural control in OSA patients during REM sleep is unlikely to explain the increased upper-airway collapse in this sleep stage. Rather, a generalized reduction in GG activity during REM likely renders individuals who are highly reliant on upper-airway dilator muscles vulnerable to pharyngeal collapse during REM sleep.

In the flicker of an eye

In the flicker of an eye

Theta and Gamma Coordination of Hippocampal Networks during Waking and Rapid Eye Movement Sleep

Rapid eye movement (REM) sleep has been considered a paradoxical state because, despite the high behavioral threshold to arousing perturbations, gross physiological patterns in the forebrain resemble those of waking states. To understand how intrahippocampal networks interact during REM sleep, we used 96 site silicon probes to record from different hippocampal subregions and compared the patterns of activity during waking exploration and REM sleep. Dentate/CA3 theta and gamma synchrony was significantly higher during REM sleep compared with active waking. In contrast, gamma power in CA1 and CA3-CA1 gamma coherence showed significant decreases in REM sleep. Changes in unit firing rhythmicity and unit-field coherence specified the local generation of these patterns. Although these patterns of hippocampal network coordination characterized the more common tonic periods of REM sleep (approximately 95% of total REM), we also detected large phasic bursts of local field potential power in the dentate molecular layer that were accompanied by transient increases in the firing of dentate and CA1 neurons. In contrast to tonic REM periods, phasic REM epochs were characterized by higher theta and gamma synchrony among the dentate, CA3, and CA1 regions. These data suggest enhanced dentate processing, but limited CA3-CA1 coordination during tonic REM sleep. In contrast, phasic bursts of activity during REM sleep may provide windows of opportunity to synchronize the hippocampal trisynaptic loop and increase output to cortical targets. We hypothesize that tonic REM sleep may support off-line mnemonic processing, whereas phasic bursts of activity during REM may promote memory consolidation.

An endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone across the sleep-wake cycle.

Skeletal muscle tone is modulated in a stereotypical pattern across the sleep-wake cycle. Abnormalities in this modulation contribute to most of the major sleep disorders; therefore, characterizing the neurochemical substrate responsible for transmitting a sleep-wake drive to somatic motoneurons needs to be determined. Glutamate is an excitatory neurotransmitter that modulates motoneuron excitability; however, its role in regulating motoneuron excitability and muscle tone during natural sleep-wake behaviors is unknown. Therefore, we used reverse-microdialysis, electrophysiology, pharmacological, and histological methods to determine how changes in glutamatergic neurotransmission within the trigeminal motor pool contribute to the sleep-wake pattern of masseter muscle tone in behaving rats. We found that blockade of non-NMDA and NMDA glutamate receptors (via CNQX and d-AP-5) on trigeminal motoneurons reduced waking masseter tone to sleeping levels, indicating that masseter tone is maximal during alert waking because motoneurons are activated by an endogenous glutamatergic drive. This wake-related drive is switched off in non-rapid eye movement (NREM) sleep, and this contributes to the suppression of muscle tone during this state. We also show that a functional glutamatergic drive generates the muscle twitches that characterize phasic rapid-eye movement (REM) sleep. However, loss of a waking glutamatergic drive is not sufficient for triggering the motor atonia that characterizes REM sleep because potent activation of either AMPA or NMDA receptors on trigeminal motoneurons was unable to reverse REM atonia. We conclude that an endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone during wakefulness, NREM sleep, and phasic REM sleep but not during tonic REM sleep.

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.

High frequency activities in the human orbitofrontal cortex in sleep–wake cycle

We recorded human orbitofrontal electrocorticogram during wakefulness and sleep in epileptic patients using subdural electrodes. During wakefulness and rapid eye movement (REM) sleep, we observed beta activity in the raw orbitofrontal signals. Power spectral analysis demonstrated beta enhancement during wakefulness and REM sleep when compared to slow wave sleep (SWS). During the phasic REM periods, the beta power was significantly lower than during the tonic REM periods. Gamma enhancement manifested itself in four out of six subjects during the phasic periods. This study is the first that has focused on electrical activity in the human orbitofrontal cortex. Although the role of the orbitofrontal cortex during sleep still remains unclear, high frequency activities give us important suggestions in elucidating the human sleep mechanism.

Serotonergic antidepressants are associated with REM sleep without atonia.

Rapid eye movement (REM) sleep behavior disorder (RBD) is generally observed in older men and in individuals with specific neurologic diseases. There are case reports of RBD in individuals taking serotonergic antidepressants. Our objective was to assess electromyogram (EMG) activity during REM sleep in individuals taking serotonergic antidepressants and in a matched control group not on such medication. Chart review of clinical and polysomnographic data. Sleep laboratory affiliated with a general hospital. 15 subjects taking a serotonergic antidepressant and 15 age-matched individuals not on such medication. Submental and anterior tibialis tonic and phasic EMG activity during REM sleep, REM latency, time in REM, apnea-hypopnea index, periodic leg movements of sleep index, and sleep-architecture measures. Tonic, but not phasic, submental EMG activity during REM sleep was significantly more common in the antidepressant-treated group than in the control group (P < .02). Tonic REM submental EMG activity correlated with REM latency (r = .42, P = .02) and inversely with REM time (r = -.36, P = .05). Subject age correlated with tonic REM submental EMG activity (r = .58, P = .02) in the antidepressant group There were also trends for more phasic activity in the anterior tibialis (P = .09) and submental (P = .07) EMG in REM sleep in the antidepressant group than in the control group. Subjects taking serotonergic antidepressants had more EMG activity in the submental lead during REM sleep than did controls. This correlated with measures of REM suppression and age. Individuals taking such medications may be at increased risk of developing REM sleep behavior disorder, particularly with increasing age.