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Volume 12 No. 06
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Scientific Investigations

Does Postural Rigidity Decrease during REM Sleep without Atonia in Parkinson Disease?

http://dx.doi.org/10.5664/jcsm.5882

Dario Arnaldi, MD1,2; Alice Latimier, MS3; Smaranda Leu-Semenescu, MD1,3; Fabrizio De Carli, MPhys4; Marie Vidailhet, MD, PhD3,5; Isabelle Arnulf, MD, PhD1,3
1APHP- Pitié-Salpêtrière Hospital, Sleep Disorders Unit, Paris, France; 2Clinical Neurology, Department of Neuroscience (DINOGMI), University of Genoa, Italy; 3Brain Research Institute- UPMC Paris 6 Univ, Inserm U 1127; CNRS UMR 7225, IHU neuroscience, Paris, France; 4Institute of Bioimaging and Molecular Physiology, National Research Council, Genoa, Italy; 5APHP- Pitié-Salpêtrière Hospital, Neurology Department, Paris, France

ABSTRACT

Study Objectives:

Rigidity is a muscle hypertonia typical of Parkinson disease (PD), whereas rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by abnormally increased muscle tone during REM sleep (REM sleep without atonia) and enacting dream behaviors. Because movements are not bradykinetic during RBD in patients with PD, we investigated whether the background, wake postural rigidity is attenuated during REM sleep without atonia, in absence of movement.

Methods:

The amplitude of levator menti (postural muscle) electromyographic activity during relaxed evening wakefulness (considered as reference) and sleep (N2, N3, atonic REM sleep, and quiet REM sleep without atonia) was measured in 20 patients with PD (with and without RBD), 10 patients with idiopathic RBD patients and 10 healthy subjects.

Results:

The chin tone amplitude progressively decreased from wake to N2, N3, and atonic REM sleep in the four groups, but the highest amplitude was observed in PD patients with RBD during atonic REM sleep. Furthermore, chin muscle tone amplitude did not attenuate from wake to REM sleep without atonia in patients with both PD and RBD but dramatically attenuated (by 40% on average) in patients with idiopathic RBD.

Conclusions:

The high amplitude of chin muscle tone in PD with RBD (but not in idiopathic RBD) during REM sleep with and without atonia suggests that both PD-related hypertonia and RBD-related enhanced muscle tone coexist during REM sleep, together affecting chin muscle tone. Consequently, some rapid RBD movements likely start against a rigid postural tone.

Citation:

Arnaldi D, Latimier A, Leu-Semenescu S, De Carli F, Vidailhet M, Arnulf I. Does postural rigidity decrease during REM sleep without atonia in Parkinson disease? J Clin Sleep Med 2016;12(6):839–847.


INTRODUCTION

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by vocalization and complex motor behaviors in association with loss of normal atonia during REM sleep.1 Idiopathic RBD (iRBD) is often a preclinical manifestation of alphasynuclein-linked neurodegenerative diseases.2 RBD is also a frequent symptom in patients with fully developed Parkinson disease (PD).3 PD is a movement disorder with bradykinesia, rest tremor, postural instability, and rigidity symptoms.4 However, we recently observed that bradykinesia and tremor disappeared during RBD movements in PD patients,5,6 suggesting that the control of movements is different between wake and sleep states and facilitated during REM sleep.1 Rigidity is a cardinal clinical PD feature that is characterized by increased muscle tone, which causes resistance to externally imposed joint movements.7 However, despite an absent postural muscle tone expected during normal REM sleep,8 there is excess muscle tone during REM sleep in RBD.9 The mechanisms of these two conditions of increased muscle tone are still debated.

BRIEF SUMMARY

Current Knowledge/Study Rationale: In patients with Parkinson disease (PD), despite the rigidity and the bradykinesia, movements are rapid and not slow during rapid eye movement (REM) sleep behavior disorder (RBD). It is unclear whether wake postural rigidity is attenuated during REM sleep without atonia in patients with PDs.

Study Impact: Both PD-related (rigidity) and RBD-related (REM sleep without atonia) muscle hypertonia coexist during REM sleep suggesting that some rapid RBD movements likely occur against a rigid postural tone. This finding provides new information about postural rigidity and RBD in PD.

Wake PD-associated rigidity is related to an altered stretch reflex10 and an altered supraspinal motor drive.11 In normal subjects, postural muscle tone progressively decreases from wake to nonrapid eye movement (NREM) and REM sleep, possibly due to a passive, reduced firing of the serotonergic and glutamatergic neurons.12 Normal REM sleep atonia results from the passive cessation of serotonergic neuron firing along with an active paralysis of postural muscle tone via descending gamma-aminobutyric acid (GABA)/glycine inhibitory neurons.1 In the presence of a breakdown in the brainstem circuits controlling REM sleep atonia, the REM muscle tone may be imperfectly abolished. In PD patients with RBD, these two hypertonic conditions coexist, one during wake (muscle rigidity) and one during REM sleep state (REM sleep without atonia, RWA); however, whether the wake hypertonic condition affects the muscle tone during sleep is unknown. Measuring muscle tone amplitude with electromyography (EMG) may help in understanding these respective influences.

Thus far, EMG activity has primarily been quantified during RBD in terms of time spent with enhanced tonic and phasic activity. The EMG tone amplitude is considered a cutoff to identify tonic and phasic REM sleep activity. However, EMG amplitude quantification in RBD could provide additional information about muscle tone control. Because movements are not bradykinetic during RBD in patients with PD,6 we sought to determine whether this parkinsonism improvement also applies to postural wake rigidity. Thus, we investigated the characteristics of the chin EMG amplitude during REM sleep compared with wake in PD patients with RBD and compared these findings with those of PD patients without RBD, patients with iRBD (who have no rigidity during wake), and healthy subjects.

METHODS

Thirty patients with PD and 10 with iRBD were recruited from the Movement Disorder and Sleep unit of the Pitie-Salpetriere Hospital, respectively. Diagnosis of PD and iRBD followed current criteria.4,9 In particular, iRBD was defined by absence of any neurological disorder, as assessed by interview and full neurological and physical evaluation by neurologists, as well as normal cognitive test (Montreal Cognitive Assessment), normal 3T magnetic resonance imaging (MRI) and absence of orthostatic hypotension. Olfaction and color vision were evaluated in these patients too, but not detailed here. The patients underwent brain magnetic resonance imaging to rule out other brain diseases. In patients with PD, cognitive impairment was assessed using the Mini-Mental State Examination, and only patients with a score higher than 23 were included. Daytime sleepiness was assessed using the Epworth Sleepiness Scale. A complete neurological examination was performed in an “off state” condition and at the highest effect of dopaminergic agents (“best on state”). Parkinsonism severity was quantified using the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III), and the Hoehn and Yahr stage. The levodopa-equivalent dose was computed for each patient with PD.13 The patients were free of any antidepressant and benzodiazepine, as well as melatonin (first analysis). In addition, 10 supplementary PD patients taking selective serotonin reuptake inhibitors were separately analyzed because these drugs might increase EMG tone.14 For comparison, 10 healthy volunteers in the same age range of the patients with no history of neurological disorders and not treated by any psychotropic drugs (especially antidepressants) were recruited. All subjects provided written informed consent. The studies (Nucleipark15 and Alice16 projects) were approved by the local ethics committee.

Sleep and nocturnal movements were monitored over a single night for all subjects using video-polysomnography. The monitoring included Fp1-Cz, O2-Cz, and C3-A2 EEG, right and left electro-oculogram, nasal pressure monitoring through a cannula, tracheal sounds through a microphone, thoracic and abdominal belts for assessing respiratory efforts, electrocardiography, pulse oximetry, EEG-synchronized infrared video monitoring and an ambiance microphone. The EMG recording of the levator menti and left and right tibialis anterior muscles was monitored. Sleep stage, arousal, respiratory events, and muscle activity were scored through visual inspection according to international criteria.8 The presence or absence of RBD in PD patients was determined through clinical interview, video, and sleep monitoring.8 Ten patients with iRBD, 10 patients with PD and RBD (PD+RBD+), 10 patients with PD but no RBD (PD+RBD−), and 10 PD patients with RBD and intake of selective serotonin reuptake inhibitors were evaluated.

We selected the chin muscle for the EMG quantification because it is a postural muscle, tonically active during wakefulness and non REM sleep, and can be tonically active also during REM sleep. Notably, the aim of the study was not to study muscle tone during movements, but the background, postural muscle tone during periods without any movement (quiescent wake and REM sleep). The surface EMG recordings were calibrated and filtered with a sampling rate of 256 Hz, high-frequency filter of 100 Hz, and low-frequency filter of 10 Hz. The quantification of time spent with enhanced tonic and phasic EMG activity during REM sleep was performed manually according to Montplaisir et al., using 30-sec epochs.17 EMG amplitude was manually collected during closed eyes, stable, quiet wake without any movement before sleep in the evening (evening wake), NREM stage 2 (N2), NREM stage 3 (N3), REM sleep with atonia (atonic-REM), stable RWA without any movement and with eyes closed, quiet wake after sleep in the morning (morning wake), all in the recumbent dorsal position. A stable 5-sec miniepoch was selected for each stage by a rater blind to the patient medical status. All artifacts and increases in EMG tone due to arousals from respiratory events, snoring, or movements and due to electrocardiography were excluded from the quantitative EMG scoring. Ten EMG amplitude measurements were collected in each stage-specific 5-sec mini-epoch, by selecting the higher waves but excluding the artifacts. The EMG amplitudes were measured as the difference between the minimum and maximum waves' amplitude, in microvolts. The mean of the amplitude measurements for each stage was computed for each subject. Both atonic-REM and RWA were measured in two different 5-sec miniepochs, arbitrarily chosen in the final sleep cycle, after at least one 30-sec epoch of stable REM sleep. We chose the final REM sleep episode because it is usually more stable and longer, and to ensure consistency across patients. For RWA, only tonic EMG activity was considered. When possible, N2 and N3 measurements were collected in the same sleep cycle. If not, the previous sleep cycle was used for NREM measurement. Some epochs containing enhanced muscle tone could always be detected, even in PD+RBD− patients and healthy controls, but were present in these last cases (due to the definition of abnormal RWA in RBD), during less than 14% of REM sleep. Indeed, to diagnose RBD, patients should exhibit at least 14% of REM sleep with any (tonic/phasic) EMG chin activity, or > 27% with any chin EMG activity combined with bilateral phasic activity of the flexor digitorum superficialis muscles.18 Figure 1 and Figure 2 depict examples of 30-sec epochs of the sleep stages. Figure 3 shows an example of a 5-sec miniepoch. To circumscribe the methodological bias caused by between-individual differences in levator menti anatomy and the interelectrodes distance, we computed a relative EMG amplitude value in each stage, considering the evening wake EMG value as the reference. Muscle amplitude progressively decreases from wake to NREM and is lowest in REM sleep.19 Thus, evening-wake can be assumed to be the 100% maximal EMG amplitude of the subsequent sleep stages. Therefore, the relative EMG amplitude of each stage was computed as the ratio between the amplitude of the given stage and evening-wake amplitude*100. We checked for the stability of the signal and putative changes in cutaneous resistance across the night by comparing evening and morning muscle tone.

Examples of 30-sec epochs of wake, N2, N3 atonic REM, and RWA in a control patient and a patient with PD+RBD+.

For the control RWA stage, an example of increased EMG tone not sufficient to score as a RWA epoch is shown. For the patient with PD+RBD+, a low chin EMG tone according to international criteria (i.e., baseline EMG activity in the chin derivation no higher than in any other sleep stage and usually at the lowest level of the entire recording) is shown. However, the atonic-REM EMG tone appears higher in the patient with PD+RBD+ compared with the control patient. EMG, electromyography; PD, Parkinson disease; RBD, REM sleep behavior disorder; REM, rapid eye movement; RWA, REM sleep without atonia.

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Figure 1

Examples of 30-sec epochs of wake, N2, N3 atonic REM, and RWA in a control patient and a patient with PD+RBD+.

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Examples of 30-sec epochs of atonic REM and RWA with superimposed phasic activity in a patient with iRBD and one with PD+RBD+.

iRBD, idiopathic REM sleep behavior disorder; PD, Parkinson disease; REM, rapid eye movement.

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Figure 2

Examples of 30-sec epochs of atonic REM and RWA with superimposed phasic activity in a patient with iRBD and one with PD+RBD+.

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Example of a 5-sec miniepoch.

The full arrow indicates a probable electrocardiogram (EKG) artifact whereas the dotted arrow indicates a wave included in the samples. After the waves were selected, we manually measured the peak-to-peak amplitude, in microvolts, by using the cursor of the scoring software (Medatec, France). EEG, electroencephalogram; EMG, electromyogram; EOG, electrooculogram.

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Figure 3

Example of a 5-sec miniepoch.

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The absolute EMG amplitude values were compared across wake and sleep stages with a repeated-measures univariate analysis of variance (ANOVA) in each study group. The differences between absolute EMG evening and morning wake and between absolute EMG RWA and both absolute EMG evening and morning wake were evaluated with a paired t-test in each study group. The relative EMG amplitude values at each stage and tonic and phasic REM EMG activity were compared between the four groups by ANOVA. The demographic and sleep characteristics of the subjects were compared between groups using ANOVA (continuous measures) and chi-square test (categorical measures). Pearson correlations between both relative atonic-REM and RWA EMG values and age or UPDRS-III scores were assessed. The clinical characteristics of PD patients were compared by unpaired t-test. The normality assumption for ANOVA was checked by applying the Bartlett test to the residuals. To prevent the multiple comparison problem, a probability value lower than 0.005 was considered statistically significant for the EMG features ANOVAs. Moreover, the Tukey-Kramer method has been applied as post hoc testing of ANOVAs, using a significance level of 0.05. Statistical analysis was performed with Stata software (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP).

RESULTS

The demographic and clinical characteristics and sleep measures of the groups are shown in Table 1. Age (but not sex) was different between groups (p = 0.0007), and patients with iRBD were older than those with PD+RBD− (p < 0.001). Sleep efficiency was significantly different between groups (p < 0.001), and controls had higher efficiency than patients with PD+RBD+ (p < 0.005) and iRBD (p < 0.005). Total sleep time (TST) was significantly different between groups (p < 0.05), and controls had longer TST than patients with PD+RBD+ (p < 0.05). N2 sleep percentage was significantly different between groups (p < 0.01), and patients with iRBD had lower N2 percentages than those with PD+RBD− (p < 0.05) and PD+RBD+ (p < 0.05). N3 sleep percentage was significantly different between groups (p < 0.005), and patients with PD+RBD+ had lower N3 percentages than control patients (p < 0.01) and those with iRBD (p < 0.05). Sleepiness scores were significantly different between groups (p < 0.05), and patients with PD+RBD+ had higher sleepiness scores than control patients (p < 0.05). No significant differences were observed in apnea-hypopnea index, N1, and REM sleep percentage between groups. PD disease duration and motor severity, levodopa equivalent, sleepiness score, and cognitive score were not different between the PD+RBD− and PD+RBD+ groups.

Demographic, clinical, and polysomnographic findings in healthy control patients, patients with idiopathic REM sleep behavior disorder (iRBD), and patients with Parkinson disease without (PD+RBD−) and with RBD (PD+RBD+).

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Table 1

Demographic, clinical, and polysomnographic findings in healthy control patients, patients with idiopathic REM sleep behavior disorder (iRBD), and patients with Parkinson disease without (PD+RBD−) and with RBD (PD+RBD+).

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As expected, the percentage of tonic RWA was different between groups (p < 0.0001; Table 1). Patients with iRBD had higher tonic RWA percentages than patients with PD+RBD+ (p < 0.001), PD+RBD− (p < 0.001), and control patients (p < 0.001), and patients with PD+RBD+ had a higher tonic RWA than PD+RBD− (p = 0.005) and control patients (p = 0.001). Similarly, the percentage of phasic RWA was different between groups (p < 0.0001; Table 1). Patients with iRBD had higher phasic RWA percentages than patients with PD+RBD+ (p < 0.001) and PD+RBD− (p < 0.001), and control patients (p < 0.001), and patients with PD+RBD+ had a higher phasic RWA percentage than patients with PD+RBD− (p = 0.035) and control patients (p = 0.014).

The absolute EMG amplitude decreased from wake to N2, N3, and atonic REM sleep (p < 0.0001). Figure 4 shows the stage-specific relative EMG amplitude values across the sleep stages in each study group. No differences were observed between absolute amplitude in evening and morning wake. The absolute RWA EMG amplitude was significantly lower than both evening and morning wake (p < 0.01) in all groups except PD+RBD+. No differences between groups were observed for N2, N3, and morning wake relative EMG amplitude values.

Stage-specific relative electromyography amplitude means for the four groups.

iRBD, idiopathic REM sleep behavior disorder; PD, Parkinson disease; RBD, REM sleep behavior disorder; REM, rapid eye movement.

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Figure 4

Stage-specific relative electromyography amplitude means for the four groups.

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In contrast, the relative EMG RWA amplitude values differed between groups (Table 2, Figure 5, p = 0.0016). The muscle amplitude attenuated during RWA in patients with iRBD (63.8 ± 30% of evening wake) and did not attenuate in patients with PD+RBD+ (the relative amplitude EMG value was 101.9 ± 42% of evening wake). PD+RBD+ group showed higher values than PD+RBD− (p = 0.004), iRBD (p = 0.04) and control groups (p = 0.004). The relative EMG atonic-REM amplitude was lower (by definition) than during RWA and different between groups (Table 2, Figure 5, p = 0.0007). PD+RBD+ group showed higher values than PD+RBD− (p = 0.008), iRBD (p = 0.003), and control groups (p = 0.002).

Relative rapid eye movement sleep without atonia and atonic-rapid eye movement electromyography amplitude values (mean ± standard deviation) in the four groups.

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Table 2

Relative rapid eye movement sleep without atonia and atonic-rapid eye movement electromyography amplitude values (mean ± standard deviation) in the four groups.

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Tukey boxplot of relative muscle tone amplitude during atonic REM sleep (empty boxes) and REM sleep without atonia (dark gray) in the four groups.

The relative electromyography amplitudes are shown as a percentage of evening wake. The asterisk (*) indicates post hoc difference compared with other groups. iRBD, idiopathic REM sleep behavior disorder; PD, Parkinson disease; RBD, REM sleep behavior disorder; REM, rapid eye movement; RWA, REM sleep without atonia.

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Figure 5

Tukey boxplot of relative muscle tone amplitude during atonic REM sleep (empty boxes) and REM sleep without atonia (dark gray) in the four groups.

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No significant correlation was found between age and relative muscle amplitude in atonic-REM sleep or RWA. In contrast, the UPDRS-III “on” scores positively correlated with relative EMG atonic-REM amplitude (r = 0.40, p = 0.011) and relative EMG RWA amplitude (r = 0.32, p = 0.047).

The 10 patients in the PD+RBD+ group taking a selective serotonin reuptake inhibitor exhibited reduced REM sleep percentage (p = 0.01) and increased tonic (p = 0.002) and phasic (p = 0.02) RWA percentage compared with the 10 patients in the PD+RBD+ group (who were free of any selective serotonin reuptake inhibitor), and no differences in sex, age, Hoehn and Yahr score, UPDRS-III score, PD course, levodopa equivalent daily dose, or cognitive score were observed (Table 3). Notably, the relative EMG amplitude values did not differ between the two groups in any sleep stage.

Demographic, clinical, and polysomnographic findings in patients with Parkinson disease with rapid eye movement sleep behavior disorder (PD+RBD+) with and without selective serotonin reuptake inhibitors.

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Table 3

Demographic, clinical, and polysomnographic findings in patients with Parkinson disease with rapid eye movement sleep behavior disorder (PD+RBD+) with and without selective serotonin reuptake inhibitors.

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DISCUSSION

The amplitude of postural muscle tone does not attenuate from wake to RWA in patients with both PD and RBD but dramatically attenuates (by on average 40%) in patients with iRBD, PD patients without RBD, and controls. This finding also applies to normal atonic-REM sleep, exhibiting residual higher amplitudes of muscle tone in PD patients with RBD and tending to in PD patients without RBD, suggesting that each condition (PD and RBD) contributes to the increased amplitude of postural muscle tone during REM sleep.

During wakefulness, patients with PD suffer from continuous muscle hypertonia that clinically results in rigidity.7 Rigidity in PD has been associated with an altered central regulation of tonic reflex spatial threshold, resulting in the inability to relax muscles.20 Thus, a small, residual background muscle activity is observed in patients with PD, even when the muscle is relaxed.20 If this increased background tone is observed in patients with PD during wake, the same background hypertonia could be expected during sleep. Moreover, when a sleep-specific enhancement of muscle tone, such as RWA, due to RBD is also present, an even greater muscle tone increase should be observed. Here, PD patients with RBD exhibited an increase in both RWA and atonic-REM EMG tone compared with control, iRBD, and PD+RBD− patient groups. If this enhanced muscle tone were only due to the PD-related rigidity, an increase in EMG amplitude values should be expected in PD patients without RBD compared with subjects without PD thus without rigidity (controls and patients with iRBD). Here, no significant difference has been found in EMG amplitude values between control patients and those with iRBD and PD+RBD− (Figure 5). However, if the enhanced muscle tone found in PD patients with RBD were due to RBD-related hypertonia (i.e., RWA), the patients with RBD without PD (i.e. iRBD) should exhibit higher EMG amplitude values in comparison with the subjects without RBD (controls and PD+RBD−). However, as we already reported, no EMG amplitude differences have been found between these three groups (Figure 5).

Thus, the increase in REM sleep EMG amplitude found in patients with PD+RBD+ compared not only with controls but also with patients with PD without RBD (PD+RBD−) and patients with RBD without PD (iRBD) suggest that even if the underlying mechanisms of the PD-related and RBD-related hypertonia are different, their effects are augmented by each condition. Whether these two mechanisms have reciprocal neurophysiological interactions or shared common pathological dysfunction must be further investigated.

The mechanism of the increased muscle tone (even when slightly enhanced during atonic-REM sleep) in PD patients with RBD is unknown. One may look at serotoninergic and dopaminergic influences on postural muscle tone during wake and sleep. It is intriguing to note that the stage-specific decrease of relative EMG amplitude fits with the serotonergic and glutamatergic neurons firing decrease from wake to NREM and REM sleep.12,21 The descending serotonergic neurons are believed to be responsible for the passive mechanism of normal REM atonia.1,21,22 Here, SSRI use increased the percentage of phasic and tonic RWA, as shown previously by others,14 but did not increase the relative EMG amplitude in REM sleep, regardless of whether it was atonic or without atonia. Thus, the nonattenuation of muscle tone amplitude from wake to REM sleep in PD+RBD+ patients without selective serotonin reuptake inhibitors is likely not due to abnormal residual serotonergic tone during REM sleep. Moreover, the serotonergic system is not hyperactive in RBD, regardless of whether patients have PD23 or iRBD24; thus, others neurotransmitters are likely involved.

Dopamine deficiency could be responsible for this lack of EMG amplitude attenuation from wake to RWA in our patients because we observed this phenomenon in patients with PD+RBD+ (who are dopamine-deficient) and not in patients with iRBD who are not yet or only mildly dopamine-deficient (although a formal DaTscan was not perform to support this concept). However, the iRBD group had higher phasic and tonic RWA percentage. If the postural neck muscle in parkinsonian primates (intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is observed, EMG amplitude is dramatically and continuously increased compared with the basal, nondopa-mine-deficient conditions, suggesting that high rigidity (which is difficult to evaluate in primates in the absence of relaxation during passive movements of the joints) parallels the observed bradykinesia.25,26 Notably, there is a mild but clear, continuous enhancement of muscle tone amplitude during NREM and REM sleep (in absence of RBD) in these animals, suggesting a minor but noticeable role of the dopaminergic system in the control of muscle tone amplitude during sleep.25,26 One may therefore hypothesize that the nonattenuation of muscle tone amplitude from wake to RWA is at least partially linked to dopamine deficiency in PD patients with RBD. In this direction, the REM sleep muscle tone amplitude in our patients with PD increased with more severe motor disability (which is proportional to the dopaminergic deficiency).27 Notably, dopamine neurons are the only neurons among all monoamine (histamine, norepinephrine, epinephrine, serotonin) neurons that do not cease firing during REM sleep.28 Whether they contribute to a small degree to lower muscle tone during REM sleep is unclear. Notably, dopamine replacement (by levodopa or pramipexole) has a marginal but mild beneficial effect on RBD.29 In our study, the amplitude of REM sleep muscle tone was measured during the final REM sleep episode to ensure that the dopamine nocturnal levels were at their lowest (“worst off” condition) in these treated patients.

GABA- and glycine-mediated inhibition of spinal moto-neurons are strong candidates for the underlying mechanism of REM muscle atonia.30 A breakdown of normal GABA and glycine circuit appears to be related to excessive phasic movements rather than tonic muscle increases in RBD.30 Murine models with lesions in the glutamatergic ventral sublaterodorsal nucleus (which stimulates the GABA/glycine neurons of the medulla) exhibit RWA and RBD-like behaviors.31 In humans, this nucleus is equivalent to the locus subcoeruleus. Significant decreased neuromelanin-sensitive MRI signal in this area is observed in PD patients with RBD compared with those without RBD and healthy subjects.15 Moreover, reduced signal intensity specifically correlates with RWA percentage.15 However, the relationship between locus subcoeruleus signal intensity and RWA amplitude is unknown.

The cholinergic system is also involved in the control of REM sleep atonia, at least in feline models. Indeed, muscle atonia and REM sleep are immediately elicited when carbachol (a muscarinic agonist) is injected into the subcoeruleus nucleus.32 Cholinergic system involvement in RBD pathophysiology has been suggested in PD with RBD23 and in iRBD.33 However, a recent neuropathological study found no difference in brainstem cholinergic nuclei between Lewy body disease patients with or without RBD.34 Thus, cholinergic involvement in REM sleep muscle tone dysfunction in RBD remains debated, even if drugs, such as clomipramine, which has an anticholinergic effect, could increase RWA.35

What could be the consequence of this nonattenuation of EMG amplitude from wake to RWA in PD patients with RBD, and how could this phenomenon influence RBD movements? We previously observed that movements during RBD (unlike wake and arousals movements) are not bradykinetic in patients with PD but are rapid and somehow jerky.5,6,36 Moreover, no tremor is visible during REM sleep, even during relaxed RWA. However, tremor rapidly reappears upon awakening.36 During RBD, movements are associated with phasic, high activity on corresponding EMG recordings, whether on limb muscles during limb movements or the chin during speaking or chewing.37 Movements usually start against two opposite background conditions during RBD: against a completely atonic background (phasic without preceding tonic activity) or against a tonic background (Figure 2).3 In the first case, one expects the movements to be easier because they occur against a very low rigidity. However, in the second case (phasic movements superimposed on a tonic EMG), they operate against a postural tone as ample as during wakefulness because the postural muscle tone is not fully attenuated. We suspected that the rapid movements during RBD are not influenced by the basal ganglia (otherwise, they would be bradykinetic in patients with PD) and that they may result from a direct descending input from the premotor cortex.1,6 This hypothesis has been recently supported by functional imaging during RBD in four patients (with iRBD, PD, and narcolepsy).38 In all of these patients, movements during RBD elicited a bilateral activation of the premotor cortex, interhemispheric cleft, periacqueductal area, ventral and rostral pons, and cerebellum but notably, not the basal ganglia. However, if RBD movements in patients with PD are rapid, they are not totally normal and smoothed as in awake, healthy subjects. They are often jerky and duplicated. The absence of motor message filtering through the basal ganglia may contribute to this unique shape of the movements and possibly the increased muscle tone amplitude background when phasic rapid activity occurs against tonically increased muscle tone. In this last case, the postural rigidity that persists in RWA likely has a different mechanism and opposite link with the basal ganglia than movements in RBD.

We also found that patients with iRBD exhibited higher amount of both tonic and phasic REM compared with the other groups (Table 1). This is in line with literature data.37,39 This finding could be, at least in part, explained by a referral bias. In fact, patients with iRBD usually seek medical attention when the severity of the disease is moderate or severe40 whereas patients with PD refer to medical consultation for the motor symptoms and the sleep problems could be disclosed even in milder forms. Indeed, a recent study has shown that surface EMG activity in REM sleep is related to RBD disease severity.41

A limitation of the study is that we arbitrarily selected the number of the samples to be studied in each stage and that only the last REM sleep has been studied. This selection has allowed consistency across patients; however, a confirmation of the current finding could be performed with different selections and/or with a computerized instead of manual measurement method.

In conclusion, we found that PD patients with RBD have no attenuation of muscle amplitude from wake to RWA compared with PD patients without RBD, with iRBD, and controls. This finding suggests that both PD-related (possibly linked to the dopamine but not serotonin deficiency) and RBD-related (possibly linked to breakdown in atonia pathways, including acetylcholine, glutamate and GABA/glycine) muscle hypertonia coexist during REM sleep. This absence of attenuation may contribute to the abnormal shape of some movements during RBD but does not facilitate their rapidity because they may operate against a more rigid background. It would be interesting to follow over years whether this 40% attenuation of muscle tone from wake to tonic RWA in patients with iRBD progressively disappears when they convert to PD. Finally, our data suggest that the quantification of chin EMG amplitude during REM sleep could provide useful information in understanding the underlying mechanisms of RBD.

DISCLOSURE STATEMENT

This was not an industry supported study. The work was supported by Agence Nationale de la Recherche (ANRMNP 2009, Nucleipark), DHOS-Inserm (2010, Nucleipark), France Parkinson (2008) and IHU de Neurosciences, and NRJ12 Institute of France Prize to Isabelle Arnulf. Dr. Vidailhet has consulted for Merck and received national grant (ANR) and patient's association research grant (Amadys, APTES). Dr. Arnulf has consulted and participated in speaking engagement for UCB. The other authors have indicated no financial conflicts of interest.

ABBREVIATIONS

ANOVA

analysis of variance

EEG

electroencephalography

EMG

electromyography

GABA

gamma-aminobutyric acid

iRBD

idiopathic REM sleep behavior disorder

NREM

non rapid eye movement

PD

Parkinson disease

PD+RBD+

patients with Parkinson disease and REM sleep behavior disorder

PD+RBD−

patients with Parkinson disease but no REM sleep behavior disorder

REM

rapid eye movement

RBD

REM sleep behavior disorder

RWA

REM sleep without atonia

UPDRS-III

United Parkinson disease rating scale-part III

ACKNOWLEDGMENTS

Author contributions: 1) Research project: A. Conception, B. Organization, C. Execution; 2) Statistical analysis: A. Design, B. Execution, C. Review and Critique; 3) Manuscript: A. Writing of the first draft, B. Review and Critique. Dario Arnaldi: 1B, 1C, 2A, 2B, 3A, Alice Latimier: 1B, 3B, Smaranda Leu-Semenescu: 1B, 3B, Fabrizio De Carli : 2B, 2C, 3B, Marie Vidailhet: 1A, 3B, and Isabelle Arnulf: 1A, 2A, 3A.

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