Excessive Muscle Activity Increases Over Time in Idiopathic REM Sleep Behavior Disorder

Study Objectives:

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by excessive electromyographic (EMG) activity due to dysfunction of the brainstem structures modulating REM sleep atonia. Patients with idiopathic RBD often develop a neurodegenerative disease, such as Parkinson disease, over the years, suggesting progression of an underlying pathologic process in the brainstem. It is unknown if the excessive EMG activity in REM sleep changes over time in patients with idiopathic RBD.

Setting:

University hospital sleep disorders center.

Participants:

Eleven patients with idiopathic RBD who were studied at baseline and after a mean follow-up of 5 years.

Interventions:

NA.

Measurements and Results:

Eleven patients with idiopathic RBD underwent polysomnography (PSG) at the moment of the diagnosis of RBD (PSG1) and after a mean follow-up of 5 years (PSG2). Tonic EMG activity in PSG1 and PSG2 was blindly quantified and compared in the mentalis muscle during REM sleep. Phasic EMG activity in PSG1 and PSG2 was blindly quantified and compared in the mentalis muscle, both biceps brachii, and both anterior tibialis during REM sleep. Patients were 9 men and 2 women with a mean age of 73.2 ± 5.4 years and a mean RBD duration of 10.7 ± 5.3 years at PSG2. In each of the 5 muscles and combination of muscles evaluated, phasic EMG activity was significantly greater in PSG2 than in PSG1 (P < 0.022 in all muscles studied). Mentalis tonic EMG activity increased from 30% to 54% (P = 0.013). No correlation was found between age of the patients and quantity of EMG activity at PSG1 (tonic; P = 0.69, phasic P = 0.89) and at PSG2 (tonic; P = 0.16, phasic; P = 0.42).

Conclusion:

Excessive tonic and phasic EMG activity during REM sleep increases over time in subjects with idiopathic RBD. This finding suggests that, in subjects with idiopathic RBD, there is an underlying progressive pathologic process damaging the brainstem structures that modulate REM sleep.

Citation:

Iranzo A; Ratti PL; Casanova-Molla J; Serradell M; Vilaseca I; Santamaria J. Excessive muscle activity increases over time in idiopathic REM sleep behavior disorder. SLEEP 2009;32(9):1149-1153.     

Phasic muscle activity during REM sleep in infancy-normal maturation and contrastive abnormality in SIDS/ALTE and West syndrome

The generation of phasic muscle activity during REM sleep is regulated by the brainstem. We proposed two sleep indices for phasic muscle activity during REM sleep, and examine their usefulness in assessing normal brainstem maturation and functional brainstem impairment during infancy. One - the dissociation index (DI) - seems to reflect maturation of the tonic inhibitory system functioning during REM sleep, and the other - % body movements in REMs bursts (%BMs-R) - to reflect that of the phasic one. In normal infants, DI showed a gradual, linear and significant increase with age, whereas %BMs-R showed a gradual and significant decrease with age. In infants with sudden infant death syndrome (SIDS) and one who had experienced apparent life-threatening events (ALTE), the DI values were lower than those in controls, although %BMs-R values were identical in the controls. In contrast, DI was variable in infants with West syndrome (WS), while %BMs-R exceeded normal values. The tonic inhibitory system seemed to be specifically involved in SIDS and ALTE, but the phasic inhibitory one in WS. Anatomical differences between these inhibitory systems are also discussed.     

Processing of auditory stimuli during tonic and phasic periods of REM sleep as revealed by event-related brain potentials

SUMMARY The brain has been reported to be more preoccupied with dreams during phasic than during tonic REM sleep. Whether these periods also differ in terms of the processing of external stimuli was examined. Event-related brain potentials (ERPs) to a frequent standard tone of 1000 Hz ( P = 97%) and infrequent deviant tones of 1100 and 2000 Hz ( P = 1.5% for each) were recorded ( n = 13) during wakefulness and nocturnal sleep. An ERP wave (called REM-P3) resembling a waking P3 wave was larger for the 2000 Hz deviant during tonic than during phasic REM sleep. Also the P210 wave was larger during tonic than during phasic REM sleep. A reliable mismatch negativity component appeared only in wakefulness. In summary, these results support the hypothesis that the brain is more 'open' for changes in an auditory input during tonic than phasic REM sleep.     

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.     

Dreamed Speech and Speech Muscle Activity

Polygraphic recordings were made in 20 normal adult female subjects and a total of 45 sleep records were obtained. Subjects were awakened in Stage REM or Stage 2 and, when they recalled dreaming, they were asked whether or not they had been speaking in their dreams. Polygraphic recordings enabled determination of the presence or absence of phasic EMG discharges in speech and nonspeech muscles (mimic muscle and extremity muscles) just prior to awakenings. Results were examined for correlation with presence or absence of speech recall by the subjects. When phasic discharges occurred in speech muscles during either Stage REM or Stage 2, recall of speech in dreams was prevalent, while such recall was not observed when discharges occurred in nonspeech muscles. Moreover, recall of speech in dreams was rarely observed when no muscle phasic discharges occurred. These results suggest that speech in dreams may be accompanied by phasic discharges of speech muscles.     

Suppression of interictal spikes during phasic rapid eye movement sleep: a quantitative stereo‐electroencephalography study

Tonic and phasic rapid eye movement (REM) sleep seem to represent two different brain states exerting different effects on epileptic activity. In particular, interictal spikes are suppressed strongly during phasic REM sleep. The reason for this effect is not understood completely. A different level of synchronization in phasic and tonic REM sleep has been postulated, yet never measured directly. Here we assessed the interictal spike rate across non‐REM (NREM) sleep, phasic and tonic REM sleep in nine patients affected by drug resistant focal epilepsy: five with type II focal cortical dysplasia and four with hippocampal sclerosis. Moreover, we applied different quantitative measures to evaluate the level of synchronization at the local and global scale during phasic and tonic REM sleep. We found a lower spike rate in phasic REM sleep, both within and outside the seizure onset zone. This effect seems to be independent from the histopathological substrate and from the brain region, where epileptic activity is produced (temporal versus extra‐temporal). A higher level of synchronization was observed during tonic REM sleep both on a large (global) and small (local) spatial scale. Phasic REM sleep appears to be an interesting model for understanding the mechanisms of suppression of epileptic activity.     

Reduction of transcallosal inhibition upon awakening from REM sleep in humans as assessed by transcranial magnetic stimulation

STUDY OBJECTIVES: The aim of the study is to assess, in humans, transcallosal inhibition upon awakening from rapid eye movement (REM) and non-REM sleep, by paired-pulse transcranial magnetic stimulation (TMS). DESIGN: During the daytime, a baseline session of motor evoked potentials (MEPs) was recorded. During the nighttime, the TMS sessions were administered just before sleep onset and upon awakenings from REM and stage 2 sleep, both in the early and final part of night. SETTING: The sleep research laboratory at the University of Rome "La Sapienza." PARTICIPANTS: Ten right-handed subjects participated in the experiment for 4 consecutive sleep-recording nights. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: During the daytime, a robust transcallosal inhibition was found; the MEP amplitude reduction ranged from 35% to 40%. During the nighttime, a decrease of transcallosal inhibition from right-to-left motor cortex, as compared to that from left-to-right motor cortex, was observed. The direct assessment of MEP changes, as a function of sleep stage and of the time of night, pointed to a drop of transcallosal inhibition after awakening from REM sleep. Therefore, the inhibitory activity of transcallosal fibers observed after non-REM awakening almost disappeared after REM sleep awakenings. CONCLUSIONS: The drastic drop of transcallosal inhibition after awakenings from REM sleep represents the first evidence in humans of a change of interhemispheric connectivity mediated by the corpus callosum during this sleep stage and may open new avenues for a better understanding of some aspects of sleep mechanisms (ie, dreaming function and dream mentation).     

Tonic inhibition and ponto-geniculo-occipital-related activities shape abducens motoneuron discharge during REM sleep

Eye movements, ponto-geniculo-occipital (PGO) waves, muscular atonia and desynchronized cortical activity are the main characteristics of rapid eye movement (REM) sleep. Although eye movements designate this phase, little is known about the activity of the oculomotor system during REM sleep. In this work, we recorded binocular eye movements by the scleral search-coil technique and the activity of identified abducens (ABD) motoneurons along the sleep–wake cycle in behaving cats. The activity of ABD motoneurons during REM sleep was characterized by a tonic decrease of their mean firing rate throughout this period, and short bursts and pauses coinciding with the occurrence of PGO waves. We demonstrate that the decrease in the mean firing discharge was due to an active inhibition of ABD motoneurons, and that the occurrence of primary and secondary PGO waves induced a pattern of simultaneous but opposed phasic activation and inhibition on each ABD nucleus. With regard to eye movements, during REM sleep ABD motoneurons failed to codify eye position as during alertness, but continued to codify eye velocity. The pattern of tonic inhibition and the phasic activations and inhibitions shown by ABD motoneurons coincide with those reported in other non-oculomotor motoneurons, indicating that the oculomotor system – contrary to what has been accepted until now – is not different from other motor systems during REM sleep, and that all motor systems are receiving similar command signals during this period.     

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.     

Inhibitory and excitatory intracortical circuits across the human sleep–wake cycle using paired-pulse transcranial magnetic stimulation

Studies using single-pulse transcranial magnetic stimulation (TMS) have shown that excitability of the corticospinal system is systematically reduced in natural human sleep as compared to wakefulness with significant differences between sleep stages. However, the underlying excitatory and inhibitory interactions on the corticospinal system across the sleep–wake cycle are poorly understood. Here, we specifically asked whether in the motor cortex short intracortical inhibition (SICI) and facilitation (ICF) can be elicited at all in sleep using the paired-pulse TMS protocol, and if so, how SICI and ICF vary across sleep stages. We studied 28 healthy subjects at interstimulus intervals of 3 ms (SICI) and 10 ms (ICF), respectively. Magnetic stimulation was performed over the hand area of the motor cortex using a focal coil and evoked motor potentials were recorded from the contralateral first dorsal interosseus muscle (1DI). Relevant data was obtained from 13 subjects (NREM 2: n = 7; NREM 3/4: n = 7; REM: n = 7). Results show that both SICI and ICF were present in NREM sleep. SICI was significantly enhanced in NREM 3/4 as compared to wakefulness and all other sleep stages whereas in NREM 2 neither SICI nor ICF differed from wakefulness. In REM sleep SICI was in the same range as in wakefulness, but ICF was entirely absent. These results in humans support the hypothesis derived from animal experiments which suggests that intracortical inhibitory mechanisms are involved in the control of neocortical pyramidal cells in NREM and REM sleep, but along different intraneuronal circuits. Further, our findings suggest that cortical mechanisms may additionally contribute to the inhibition of spinal motoneurones in REM sleep.     

Supraspinal control of transmission in the polysynaptic reflex pathway to motoneurones during sleep

Summary Experiments were performed to find out whether supraspinal inhibitory influences affect spinal interneurones during physiological sleep. Single shock stimulation of the tibial nerve elicits a direct motor action potential from the intrinsic plantar muscles, followed by two reflex action potentials. The early response is due to monosynaptic excitation of the spinal motoneurones, while the late response is referred to polysynaptic excitation of the same pool of motoneurones. It was then possible tos tudy the modulation of monosynaptic and polysynaptic reflexes involving the same motoneuronal population during the same episodes of sleep. In unrestrained, unanaesthetized cats both reflexes may be slightly depressed during desynchronized sleep, while a prominent phasic depression occurs at the time of the bursts of rapid eye movements (REM). There is, however, a striking difference in the amount of depression of the two reflexes during REM, since the polysynaptic reflex is more strongly depressed than the monosynaptic. It has been previously shown that the phasic depression of the spinal reflexes is due to presynaptic inhibition of the primary afferents. The greater depression of the polysynaptic reflex during REM can be referred to additional events possibly leading to postsynaptic inhibition of the interneurones of the polysynaptic reflex pathway to spinal motoneurones.Fellow of the Opera Universitaria.     

Variations in Behavioral Response Threshold Within the REM Period of Human Sleep

Behavioral response threshold measures were compared between REM tonic, REM phasic, as well as NREM-2 sleep. Eighteen young college males were each instructed to respond with one or two microswitch presses upon detection of either of two tones triggered during two non-consecutive nights of sleep in the laboratory. Repeated measures comparisons (ANOVA) of average response threshold values, as determined via a method of limits procedure, showed REM tonic values to be significantly lower than both REM phasic and NREM-2 values while the latter two did not differ significantly from each other. The average of REM period threshold values was significantly lower than NREM-2 values, solely by virtue of the tonic component of the REM period. These differences within the REM period may account in part for greater variance in REM-period behavioral thresholds within and between similar studies. This consideration deserves attention in any attempt to compare the REM period as a whole to NREM-2 stage measures of responsiveness.     

Phasic motor activity reduction occurring with horizontal rapid eye movements during active sleep in human

We describe the phasic reduction of motor activity occurring with horizontal rapid eye movements (REMs) during active sleep in 15 children (12 healthy children and 3 patients with severe brain damage). A REM-related decrease in intercostal muscle activity was demonstrated by averaging integrated surface electromyograms. In the healthy subjects, this reduction had a mean latency from the REM onset of 37.1 ms and a duration of 225.9 ms. This phenomenon was also observed in the 3 patients who had lost cerebral function. We hypothesized a brainstem origin for the effect. A REM-related mentalis muscle activity loss, detected by averaging mentalis muscle twitches, was observed in 10 healthy children among the subjects. This loss began at 59.1 ms before the onset of REMs and lasted for 230.2 ms on average. In addition, a transient decrease in integrated REM activity surrounding mentalis muscle twitches (a twitch-related reduction of REMs) was observed. We discuss the similarity between REM-related phasic reduction of muscle activity obtained for intercostal and mentalis muscles and pontogeniculo-occipital (PGO) wave-related inhibitory postsynaptic potentials reported for feline lumbar and trigeminal motoneurons, respectively. We then assume the presence of a phasic event generator, functioning during active sleep in healthy humans, which triggers at least three generators; that is, the generator of PGO waves (or REMs), motor inhibition, and of motor excitation including muscle twitches.     

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.     

Modification of EEG asymmetry induced by auditory biofeedback loop during REM sleep in man

Several studies have emphasized the relationship between (1) rapid eye movement sleep (REM sleep) and learning, and (2) between REM sleep and asymmetry in EEG activity. Since we have shown that obtaining operant conditioned responses via auditory biofeedback during REM sleep is feasible, we demonstrate here that REM contingent auditory stimulations (white noise stimulation or interruption of a continuous white noise stimulation) lead to differential changes in phasic and tonic components of REM sleep. Whereas during baseline nights a relative right activation is found in the medium bands of EEG frequencies, our procedure seems to induce a systematic interhemispheric change during experimental nights. A new approach to the information processing hypothesis during REM sleep is proposed in terms of functional lateralized modifications of the EEG.     

Changes in reflex responses of the masseter and digastric muscles during sleep in freely behaving rabbits.

The aim of this study was to clarify the modulation of motoneuron excitability in masticatory muscles during sleep. For this purpose, changes in the reflex responses of the masseter and digastric muscles between sleep and wakefulness were studied in freely behaving rabbits. Stimulation of the jaw closing muscle spindle afferents induced the masseteric monosynaptic reflex (MMR). During quiet sleep (QS), which gradually replaced quiet wakefulness, the mean MMR amplitude showed no change. During active sleep (AS). MMR amplitudes were markedly reduced, but they were confounded by the occasional occurrence of facilitation in the amplitude. The facilitatory reflexes were often related to rapid eye movements (REMs). However, the excitatory input probably did not originate from the same region as the REM generator, since the REM and the large MMR did not always occur simultaneously. On the other hand, jaw opening reflexes remained inhibited. The results indicated that there is mainly a difference in the excitability between the two groups of motoneurons during AS; masseter motoneuron activity was inhibited but occasionally facilitated by excitatory inputs occurring in association with REMs, however, the digastric motoneuron activity was remained inhibited. The excitatory inputs may induce dysfunctional muscle contraction of the jaw closing muscles as seen in bruxism.     

Elevated PEM (phasic electromyographic metric) rates identify rapid eye movement behavior disorder patients on nights without behavioral abnormalities

OBJECTIVE: To determine the validity of the phasic electromyographic metric (PEM) to differentiate patients with a history suggestive of rapid eye movement behavior disorder (REMBD) on laboratory nights without overt dream-enactment behavior. METHODS: PEM was quantified as the % of 2.5-sec intervals with phasic muscle activity of 100-msec duration with an amplitude of at least 4 times background activity in 11 patients and 31 elderly controls. Data were derived from both REM and NREM sleep from 5 muscle groups (mentalis, left/right anterior tibialis, left/right brachioradialis). RESULTS: Relative to controls, REMBD patients had significantly higher levels of PEM activity in all recordings. The largest differences occurred during REM sleep for the mentalis and brachioradialis channels. Similar results were obtained by limiting quantification of PEM to the final REM period of the night and could be accomplished by individuals with no previous familiarity with polysomnography. DISCUSSION: PEM may be a useful metric to characterize the REM related phasic muscle activity on patients with a history of REMBD, even when no overt dream-enactment behaviors are detected on a laboratory night.     

Quantification of electromyographic activity during REM sleep in multiple muscles in REM sleep behavior disorder

STUDY OBJECTIVES: The aim of our study was to determine which muscle or combination of muscles (either axial or limb muscles, lower or upper limb muscles, or proximal or distal limb muscles) provides the highest rates of rapid eye movement (REM) sleep phasic electromyographic (EMG) activity seen in patients with REM sleep behavior disorder (RBD). SETTING: Two university hospital sleep disorders centers. PARTICIPANTS: Seventeen patients with idiopathic RBD (n = 8) and RBD secondary to Parkinson disease (n = 9). INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: Patients underwent polysomnography, including EMG recording of 13 different muscles. Phasic EMG activity in REM sleep was quantified for each muscle separately. A mean of 1459.6 +/- 613.8 three-second REM sleep mini-epochs were scored per patient. Mean percentages of phasic EMG activity were mentalis (42 +/- 19), flexor digitorum superficialis (29 +/- 13), extensor digitorum brevis (23 +/- 12), abductor pollicis brevis (22 +/- 11), sternocleidomastoid (22 +/- 12), deltoid (19 +/- 11), biceps brachii (19 +/- 11), gastrocnemius (18 +/- 9), tibialis anterior (right, 17 +/- 12; left, 16 +/- 10), rectus femoris (left, 11 +/- 6; right, 9 +/- 6), and thoraco-lumbar paraspinal muscles (6 +/- 5). The mentalis muscle provided significantly higher rates of excessive phasic EMG activity than all other muscles but only detected 55% of all the mini-epochs with phasic EMG activity. Simultaneous recording of the mentalis, flexor digitorum superficialis, and extensor digitorum brevis muscles detected 82% of all mini-epochs containing phasic EMG activity. This combination provided higher rates of EMG activity than any other 3-muscle combination. Excessive phasic EMG activity was more frequent in distal than in proximal muscles, both in upper and lower limbs. CONCLUSION: Simultaneous recording of the mentalis, flexor digitorum superficialis, and extensor digitorum brevis muscles provided the highest rates of REM sleep phasic EMG activity in subjects with RBD.     

Low-frequency oscillations (<0.3 Hz) in the electromyographic (EMG) activity of the human trapezius muscle during sleep

The surface electromyographic (EMG) signal from right and left trapezius muscles and the heart rate were recorded over 24 h in 27 healthy female subjects. The root-mean-square (RMS) value of the surface EMG signals and the heartbeat interval time series were calculated with a time resolution of 0.2 s. The EMG activity during sleep showed long periods with stable mean amplitude, modulated by rhythmic components in the frequency range 0.05-0.2 Hz. The ratio between the amplitude of the oscillatory components and the mean amplitude of the EMG signal was approximately constant over the range within which the phenomenon was observed, corresponding to a peak-to-peak oscillatory amplitude of approximately 10% of the mean amplitude. The duration of the periods with stable mean amplitude ranged from a few minutes to approximately 1 h, usually interrupted by a sudden change in the activity level or by cessation of the muscle activity. Right and left trapezius muscles presented the same pattern of FM. In supplementary experiments, rhythmic muscle activity pattern was also demonstrated in the upper extremity muscles of deltoid, biceps, and forearm flexor muscles. There was no apparent association between the rhythmic components in the muscle activity pattern and the heart rate variability. To our knowledge, this is the first time that the above-described pattern of EMG activity during sleep is documented. On reanalysis of earlier recorded trapezius motor unit firing pattern in experiments on awake subjects in a situation with mental stress, low-FM of firing with similar frequency content was detected. Possible sources of rhythmic excitation of trapezius motoneurons include slow-wave cortical oscillations represented in descending cortico-spinal pathways, and/or activation by monoaminergic pathways originating in the brain stem reticular formation. The analysis of muscle activity patterns may provide an important new tool to study neural mechanisms in human sleep.     

A complementary relationship between wake and REM sleep in the auditory system: a pre-sleep increase of middle-ear muscle activity (MEMA) causes a decrease of MEMA during sleep

Since some evidence has supported a complementary relationship between waking and REM-sleep eye movement (variations in frequency, amplitude, or direction of waking saccades have been found to inversely affect the corresponding parameters of rapid eye movements), the present study assessed whether this relationship can also be shown for other phasic components of REM sleep, such as middle-ear muscle activity (MEMA), as a consequence of an increase of middle-ear reflex frequency during pre-sleep wake. Ten subjects were studied in three consecutive nights (one adaptation, one baseline, one experimental). In the experimental night, subjects underwent a 2-h pure-tone (1000 Hz, 90 dB SPL) auditory stimulation and MEMA was monitored every 15 min; noise exposure during daytime was also controlled. Results show that MEMA frequency during REM sleep significantly decreased during the experimental nights compared with baseline nights, while each sleep variable as well as mean daily auditory input did not present any significant difference between baseline and experimental nights. Results suggest that the complementary relationship between wake and REM sleep is not bounded to oculomotor activity, but it may also be extended at least to middle-ear muscle phasic activity. Received: 30 April 1999 / Accepted: 14 September 1999