Dr Pierre-Hervé Luppi, UMR5167 CNRS, Faculté de Médecine RTH Laennec, 7, Rue Guillaume Paradin, 69372 Lyon cedex 08, France. Email: email@example.com
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during paradoxical (REM) sleep (PS). The neuronal dysfunctions responsible for RBD are not known. In the present review, we propose an updated integrated model of the mechanisms responsible for PS and explore different hypotheses explaining RBD. We propose that RBD appears based on a specific degeneration of PS-on glutamatergic neurons localized in the caudal pontine sublaterodorsal tegmental nucleus or the glycinergic/GABAergic premotoneurons localized in the medullary ventral gigantocellular reticular nucleus.
Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by the acting out of dreams that are vivid, intense, and violent. Dream-enacting behaviors include talking, yelling, punching, kicking, sitting, jumping from bed, arm flailing, and grabbing. The person may be awakened or may wake up spontaneously during the acting and vividly recall the dream that corresponds to the physical activity. RBD is usually seen in middle-aged to elderly men.1 The disorder may occur in association with various degenerative neurological conditions such as Parkinson disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB).2
Rapid eye movement sleep behavior disorder often precedes the development of these neurodegenerative diseases by several years. It has been reported that up to 65% of patients diagnosed with RBD subsequently developed PD within an average time of 12–13 years from the onset of RBD symptoms. The prevalence of RBD is of 46–58% in PD, 50–80% in DLB and 90–100% of MSA patients.2 A mild form of RBD has also been identified in narcoleptics.3 An acute form may also occur during alcohol or sedative-hypnotic withdrawal, tricyclic antidepressant (such as imipramine), or serotonin reuptake inhibitor use (such as fluoxetine, sertraline, or paroxetine) or other types of antidepressants (mirtazapine). Clonazepam, a benzodiazepine, is highly effective in the treatment of RBD, relieving symptoms in nearly 90% of patients with little evidence of tolerance or abuse.2 It has been further showed that clonazepam decreases the phasic, but no the tonic, electromyographic activity in the submentalis muscle during REM sleep.4 Melatonin is also effective in some patients with RBD.5 Its beneficial effect occurs within the first week of treatment. Unlike clonazepam, melatonin decreases the tonic, but not the phasic, electromyographic activity in the submentalis muscle in subjects with RBD.2
2 BRAINSTEM STRUCTURES POTENTIALLY INVOLVED IN RBD
Several studies indicate that it is unlikely that RBD appears based on a dysfunction of the dopaminergic nigrostriatal system. The strongest arguments are that RBD does not occur in about half of the PD patients and the use of dopaminergic agents usually does not improve RBD.2
The glutamatergic neurons of the sublaterodorsal tegmental nucleus
In 1959, Jouvet and Michel discovered in cats paradoxical sleep (PS), a sleep phase characterized by a complete disappearance of muscle tone, paradoxically associated with a cortical activation and REM.6,7 Soon after, they demonstrated that the brainstem is necessary and sufficient to trigger and maintain PS in cats. Using electrolytic and chemical lesions, it was then evidenced that the dorsal part of pontis oralis (PnO) and caudalis (PnC) nuclei contains the neurons responsible for PS onset.8 Unit recordings in freely moving cats demonstrated that many neurons (called “PS-on” neurons) in this region later named in rats sublaterodorsal tegmental nucleus (SLD) show a tonic firing selective to PS.9 Two types of PS-on neurons were segregated. The first ones were restricted to the rostro-dorsal SLD and project to rostral brain areas including the intralaminar thalamic nuclei, the posterior hypothalamus and the basal forebrain. The second type of PS-on neurons recorded over the whole SLD projected caudally to the ventromedial medullary reticular formation.10 It has been proposed that (i) the ascending PS-on neurons are responsible for the cortical activation during PS; and (ii) the descending PS-on neurons generate muscle atonia during PS through excitatory projections to medullary glycinergic premotoneurons.11–14
In full agreement with unit recording studies done in cats, we found out that the SLD is the only pontine reticular structure containing a cluster of Fos-labeled neurons after PS hypersomnia thus confirming that it contains PS-on triggering PS. We further showed that these neurons are not cholinergic15 or GABAergic.16 Then, Lu et al.17 reported for the first time the presence of vGlut2 containing neurons in the SLD. We recently further demonstrated that most of the Fos-labeled neurons localized in the SLD after PS recovery express vGlut2.18 Altogether, these results indicate that the PS-on SLD neurons triggering PS are glutamatergic.
In neurodegenerative diseases where RBD is frequent, neuronal cell loss was observed in the brainstem structures modulating PS, like the locus subcoeruleus, the pedunculopontine nucleus and the gigantocellular reticular nucleus, and also in their rostral afferents, especially the amygdala.2 In cats and rats, electrolytic and neurochemical lesions limited to the SLD eliminate the tonic muscle atonia and induce phasic muscle activity during PS. The phasic events include large limb twitches, locomotion, fear, attack and defensive behaviors.17,19–21 Importantly, larger lesions induce a decrease in the total quantities of PS17,22,23 whereas RBD patients display normal quantities of PS.24 From these and our own experimental data, we propose that RBD in patients without atonia during PS could be because of a lesion of a subpopulation of PS-on glutamatergic neurons of the SLD responsible of inducing muscle atonia via their descending projections to the premotor GABA/glycinergic neurons of the GiV (see below). It implies that PS-on neurons of the SLD are divided in at least two subpopulations, one descending responsible for muscle atonia and the other one inducing the state of PS itself and electroencephalogram activation (Fig. 1). Data obtained in cats support the existence of these two populations of SLD PS-on cells (see above) but they have not been identified in rats. If these two populations exist, it remains to be discovered why only the descending SLD neurons would be destroyed in RBD patients. In any case, RBD patients should not have a large lesion of the SLD and surrounding nuclei as they do not display a decrease in total PS amount.
The glycinergic/GABAergic neurons of the medullary ventral gigantocellular nucleus
A number of results indicate that SLD PS-on glutamatergic neurons generate muscle atonia and sensory inhibition via descending medullary projections to GABA/glycinergic neurons. Indeed, it has been shown that the SLD sends direct efferent projections to glycinergic neurons in the ventral (GiV) and alpha (Gia) gigantocellular reticular nuclei. Further, glutamate release in the GiV and Gia increases specifically during PS.25 In addition, injection of non-NMDA glutamate agonists in these nuclei suppresses muscle tone while an increased tonus is seen during PS in cats with Gia and GiV cytotoxic lesion.26,27 Besides, glycinergic neurons of the Gia, GiV and nucleus raphe magnus (RMg) express c-Fos after induction of PS by bicuculline (Bic, a GABAa antagonist) injection in the SLD.28 Further, glycinergic neurons of these structures monosynaptically project to lumbar spinal motoneurons29 but also to the superficial dorsal horn involved in sensory processing.30 These results combined with others showing that sensory inputs are decreased during PS31 suggest that Gia, GiV and RMg glycinergic neurons not only hyperpolarizes motoneurons but also dorsal horn sensory neurons. It is likely that these neurons are also GABAergic as a large majority of the c-Fos-labeled neurons localized in these nuclei after 3 h of PS recovery following 72 h of PS deprivation express the mRNA of the enzyme of synthesis of GABA (GAD67mRNA).16 The role of these neurons has been recently challenged by results showing that some SLD neurons directly project to the spinal cord and that neurotoxic lesions of the ventral medulla have no effect on PS atonia.17 However, the lesions were rostral to the GiV. In addition, it has been shown in cats using antidromic activation that SLD PS-on neurons directly project to the medulla but not to the spinal cord, whereas SLD neurons with a firing rate unrelated to PS display spinal cord projections.9 Surprisingly, it has also recently been shown that co-application by microdialysis of bicuculline and strychnine (respectively GABAa and glycine antagonists) in the trigeminal nucleus induced no effect on PS atonia.32 However, negative results obtained with microdialysis should be interpreted with caution.33 Further, the same authors recently showed that combined microdialysis of bicuculline, strychnine, and phaclophen (a GABAb antagonist) in the trigeminal nucleus restored muscle tone during PS.34 The latter data support previous results indicating that the premotoneurons responsible for muscle atonia of PS are localized in the GiV and co-release GABA and glycine.
It is therefore possible that in RBD patients the premotor GABA/glycinergic neurons of the GiV are damaged. This well fits with the fact that only the atonia is lost in RBD and not the state of PS per se (Fig. 1). Finally, neurons located in the ventral mesencephalic reticular formation could also be implicated as neurochemical lesions in this area in cats increased muscle tone and phasic muscle activity in REM sleep.35
Mechanisms responsible for phasic motor activation in RBD patients with muscle atonia
A puzzling issue is the fact that some RBD patients show intense phasic motor activation without a lost of muscle atonia. These patients could have no lesion of the SLD or its GiV relay. They could present an increase in phasic activation of the motoneurons because of either an increase in excitatory phasic inputs or a decrease in phasic inhibitory inputs or both. The presence during PS of phasic glutamate excitatory and glycine/GABA inhibitory inputs on motoneurons superimposed on a tonic inhibitory input is supported by results showing an increased number of excitatory and inhibitory postsynaptic potentials during muscle twitches and the respective decrease and increase of twitches induced by the application on motoneurons of glutamate and glycine or GABA antagonists.32,36,37 The origin of these phasic inputs is not known. However, it is likely that they are because of the activation of the classical motor pathways arising from the glutamatergic pyramidal cells of the motor cortex directly projecting to motoneurons or indirectly via glutamatergic and GABA/glycine premotoneurons located in pontine and medullary reticular nuclei and intermediate spinal cord.38 An increase of excitatory phasic inputs cannot be directly attributed to a degeneration of neurons. Therefore, it is more likely that phasic inhibitory systems have been destroyed in these patients.
Mechanisms responsible for RBD in narcoleptic patients
The RBD reported in narcoleptic is probably the result of the absence of hypocretin although it cannot be completely ruled out that the SLD-GiV atonia pathway is lesioned in these patients. One possibility is that in normal condition, Hcrt neurons [hypocretin-(orexin) containing neurons] activates the SLD-GiV pathway during PS in particular during the muscle twitches induced by a phasic glutamatergic excitation of the motoneurons (Fig. 2). Two previous study results support this hypothesis. First, although Hcrt neurons are mainly active during active waking, they display bursts of activity during the twitches of PS.39 Second, application of hypocretin in the SLD region induces PS with atonia.40
This work was supported by CNRS and University Claude Bernard of Lyon.
CONFLICT OF INTEREST
The authors have no conflict of interests to declare.