sleep disorders and diurnal sleepiness are frequent in parkinson s disease.1 polysomnography studies have shown rapid - eye - movement ( rem ) sleep dysregulation with rem sleep onset on diurnal naps2,3 and loss of muscle atonia,4 which is defined as  excessive amount of sustained or intermittent elevation of submental electromyographic tone or excessive phasic submental or limb electromyographic twitching.4 loss of rem atonia is a core phenomenon of rem sleep behavioral disorder ( rbd),5 a condition characterized by vigorous and injurious motor behaviors during rem sleep.6 the orexin system plays a key role in rem sleep regulation . the loss of orexin neurons results in narcolepsy - cataplexy , a condition characterized by severe diurnal sleepiness , rem sleep onset during daytime naps , and cataplexies . rem sleep without atonia ( rswa ) and rbd have also been reported to occur in narcolepsy.7 orexin neurotransmission has been shown to be altered in parkinson s disease ( pd).810 however , polysomnographic data were not available in these postmortem studies . furthermore , we showed that ventricular orexin levels were not correlated with mean sleep latency , suggesting that orexin deficit might not be involved in daytime sleepiness in pd.11 thus , the clinical expression of orexin deficit in pd remains unknown.12 the objective of this study was to determine whether orexin - a levels in ventricular cerebrospinal fluid ( csf ) from pd patients were correlated with rem sleep without atonia . consecutive patients with idiopathic pd13 who were scheduled for deep brain - stimulation neurosurgery were invited to participate in the study , irrespective of whether they had sleep complaints . we did not include patients taking medications known to affect sleep or rem atonia or patients with sleep apnea syndrome defined as an apnea / hypopnea index greater than ten per hour of sleep . disease severity was assessed based on the motor subscore of the unified parkinson s disease rating scale iii after overnight withdrawal of dopaminergic treatment . the study was approved by the appropriate ethics committee , and informed consent was obtained from all patients prior to study inclusion . sleep recordings were obtained during attended polysomnography 1 week before the scheduled date of neurosurgery . polysomnography included electroencephalogram recordings ( c4a1 , c3a2 , and o1o2 leads ) , two electrooculograms , one submental electromyogram ( emg ) , and bilateral anterior tibialis emgs . also recorded were nasal pressure , oral airflow , thoracic and abdominal movements , and pulse oximetry . patients took their usual pd medications and were free to go to sleep when they wanted to . sleep stages were scored by two sleep specialists who had extensive experience with recordings in pd patients ( ab and xd ) , according to the modified american academy of sleep medicine criteria,14 with allowance for rswa . rswa was scored as previously described by lapierre and montplaisir.16 tonic chin - muscle activity during rem sleep was defined as chin emg amplitude greater than twice the amplitude measured during a baseline emg signal for atonia . phasic emg events were defined as any burst of activity lasting 0.35 seconds and having amplitude greater than four times the baseline emg signal . tonic and phasic emg activities were scored from the submental emg signal per 3-second mini - epochs of rem sleep containing or not containing  any  emg activity ( tonic , phasic , or a combination of both emg activities).17 we then reported loss of rem atonia as the percentage of rem sleep mini - epochs with  any  emg activity . ventriculography performed to assist in the proper placement of an electrode in the subthalamic nucleus require the removal of csf just before the injection of the contrast agent into the ventricle . in each of our patients , 3 ml of ventricular csf was immediately frozen and stored at 80c until use for the orexin - a assay8 orexin - a ( hypocretin-1 ) was measured in crude csf using a commercially available radioimmunoassay kit ( phoenix pharmaceuticals , belmont , ca , usa ) . the detection limit was 50 pg / ml , and intra - assay variability was 5% . correlations between orexin - a levels and sleep parameters were evaluated using spearman s rank - correlation test and the nonparametric mann - whitney test . consecutive patients with idiopathic pd13 who were scheduled for deep brain - stimulation neurosurgery were invited to participate in the study , irrespective of whether they had sleep complaints . we did not include patients taking medications known to affect sleep or rem atonia or patients with sleep apnea syndrome defined as an apnea / hypopnea index greater than ten per hour of sleep . disease severity was assessed based on the motor subscore of the unified parkinson s disease rating scale iii after overnight withdrawal of dopaminergic treatment . the study was approved by the appropriate ethics committee , and informed consent was obtained from all patients prior to study inclusion . sleep recordings were obtained during attended polysomnography 1 week before the scheduled date of neurosurgery . polysomnography included electroencephalogram recordings ( c4a1 , c3a2 , and o1o2 leads ) , two electrooculograms , one submental electromyogram ( emg ) , and bilateral anterior tibialis emgs . also recorded were nasal pressure , oral airflow , thoracic and abdominal movements , and pulse oximetry . patients took their usual pd medications and were free to go to sleep when they wanted to . sleep stages were scored by two sleep specialists who had extensive experience with recordings in pd patients ( ab and xd ) , according to the modified american academy of sleep medicine criteria,14 with allowance for rswa . rswa was scored as previously described by lapierre and montplaisir.16 tonic chin - muscle activity during rem sleep was defined as chin emg amplitude greater than twice the amplitude measured during a baseline emg signal for atonia . phasic emg events were defined as any burst of activity lasting 0.35 seconds and having amplitude greater than four times the baseline emg signal . tonic and phasic emg activities were scored from the submental emg signal per 3-second mini - epochs of rem sleep containing or not containing  any  emg activity ( tonic , phasic , or a combination of both emg activities).17 we then reported loss of rem atonia as the percentage of rem sleep mini - epochs with  any  emg activity . ventriculography performed to assist in the proper placement of an electrode in the subthalamic nucleus require the removal of csf just before the injection of the contrast agent into the ventricle . in each of our patients , 3 ml of ventricular csf was immediately frozen and stored at 80c until use for the orexin - a assay8 orexin - a ( hypocretin-1 ) was measured in crude csf using a commercially available radioimmunoassay kit ( phoenix pharmaceuticals , belmont , ca , usa ) . the detection limit was 50 pg / ml , and intra - assay variability was 5% . each csf sample was tested in duplicate . correlations between orexin - a levels and sleep parameters were evaluated using spearman s rank - correlation test and the nonparametric mann - whitney test . we studied eight consecutive patients  four males and four females  whose clinical features are reported in table 1 . in all eight patients , surgery was performed under regional anesthesia between 10 am and 12 am . no patients or bed partners reported violent movements during sleep , although the spouse of patient # 7 reported limb and body jerking . orexin - a levels did not correlate with total sleep time ( p = 0.23 ) , rem duration ( p = 0.45 ) , or rem latency ( p = 0.66 ) . in contrast , orexin - a levels showed a significant positive correlation with the percentage of rem epochs without atonia , ie , percentage of 3-second mini - epochs classified as  any (  = 0.83 , p = 0.027 ) ( figure 1a ) . as previously described6,17 rswa is considered clinically significant when any submental emg activity was present for more than 18% of the total rem sleep duration . according to this criterion , four of our patients had rswa ( # 2 , # 3 , # 4 , and # 7 ) . these four patients had higher median ( interquartile range ) orexin - a levels than the four patients with rem sleep atonia ( 235 pg / ml [ 215345 ] vs 94 pg / ml [ 44147 ] ; mann  whitney test p = 0.036 , figure 1b ) . we studied eight consecutive patients  four males and four females  whose clinical features are reported in table 1 . in all eight patients , surgery was performed under regional anesthesia between 10 am and 12 am . no patients or bed partners reported violent movements during sleep , although the spouse of patient # 7 reported limb and body jerking . orexin - a levels did not correlate with total sleep time ( p = 0.23 ) , rem duration ( p = 0.45 ) , or rem latency ( p = 0.66 ) . in contrast , orexin - a levels showed a significant positive correlation with the percentage of rem epochs without atonia , ie , percentage of 3-second mini - epochs classified as  any (  = 0.83 , p = 0.027 ) ( figure 1a ) . as previously described6,17 rswa is considered clinically significant when any submental emg activity was present for more than 18% of the total rem sleep duration . according to this criterion , four of our patients had rswa ( # 2 , # 3 , # 4 , and # 7 ) . these four patients had higher median ( interquartile range ) orexin - a levels than the four patients with rem sleep atonia ( 235 pg / ml [ 215345 ] vs 94 pg / ml [ 44147 ] ; mann  whitney test p = 0.036 , figure 1b ) . our results show a significant relationship between ventricular csf orexin - a levels and rem sleep characteristics in patients with pd . despite the small number of patients our results suggest that orexin - a signaling may be associated with loss of muscle atonia during rem sleep in patients with pd . to our knowledge , this is the first study of potential correlations between ventricular csf orexin - a levels and polysomnographic data in patients with pd . we undertook this study to investigate the physiological significance of altered orexin neurotransmission in pd , which has generated controversy.12 the strength of our study is the use of ventricular csf . a previous study in pd patients found that ventricular csf orexin levels correlated with the number of orexinergic neurons.9 furthermore , while a lumbar csf study failed to report a significant correlation between orexin levels and disease severity in a large group of 62 pd patients,18 a significant correlation was reported with ventricular samples.8 the main limitations of our study are the small number of patients and the absence of control subjects . we excluded patients taking sleep - altering medications and emg activities concurrent with respiratory arousals,19 which may have further limited bias in our study . in our study , pd patients with higher ventricular csf orexin levels exhibited larger numbers of rswa epochs than did patients with lower orexin levels , suggesting that preserved orexin drive may be involved in loss of rem atonia . these results are congruent with experiments demonstrating that orexin neurons are strongly involved in muscle - tone control . orexin neurons exert a facilitating influence on muscle tone , both directly via their projections on trigeminal motor neurons20 and spinal motor neurons21 and indirectly via the locus coeruleus neurons.22 orexin injections into the locus coeruleus increase muscle tone23 and interrupt pedunculopontine nucleus - induced muscle atonia.24 however , regulation of muscle atonia relies on complex relationships and interactions between the orexin system , the locus coeruleus ( in which orexin facilitates muscle activity ) , and the pontine inhibitory area ( in which orexin inhibits muscle activity ) . our results contrast with those obtained in narcolepsy - cataplexy , in which orexin levels negatively correlated with rswa.25 however , narcolepsy - cataplexy and pd are two different diseases , and the process leading to orexinergic neuron loss is likely different . orexin neurons are the primary target of an acute and specific neuronal aggression in narcolepsy , leading to a 90% reduction in the orexin neuron pool.26 in contrast , pd is a chronic , slowly progressive neurodegenerative disease , affecting primarily dopaminergic neurons , with a process not fully understood , leading to partial ( 23%60% ) orexin neuron loss.10 as an illustration , no cataplexy has been reported in pd patients , even in patients with undetectable orexin levels.8,12 our results are also in contrast with a recent study that found similar orexin lumbar levels in five rbd patients.27 however , these patients had idiopathic rbd and no sign of pd . the loss of rem atonia in patients with higher orexin levels illustrates the complexity of the symptoms induced by altered orexin neurotransmission in pd.28 experimental trials of orexin antagonists could be of interest in the transgenic mouse model of rswa .
objectivepatients with parkinson s disease frequently complain of sleep disturbances and loss of muscle atonia during rapid - eye - movement ( rem ) sleep is not rare . 
 the orexin - a ( hypocretin-1 ) hypothalamic system plays a central role in controlling rem sleep . 
 loss of orexin neurons results in narcolepsy - cataplexy , a condition characterized by diurnal sleepiness and rem sleep without atonia . 
 alterations in the orexin - a system have been also documented in parkinson s disease , but whether these alterations have clinical consequences remains unknown.methodshere , we measured orexin - a levels in ventricular cerebrospinal fluid from eight patients with parkinson s disease ( four males and four females ) who underwent ventriculography during deep brain - stimulation surgery and performed full - night polysomnography before surgery.resultsour results showed a positive correlation between orexin - a levels and rem sleep without muscle atonia.conclusionour results suggest that high levels of orexin - a in parkinson s disease may be associated with loss of rem muscle atonia .