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Breakdown in REM sleep circuitry underlies REM sleep behavior disorder John Peever1, Pierre-Herve´ Luppi2, and Jacques Montplaisir3 1
Systems Neurobiology Laboratory, Departments of Cell and Systems Biology and Physiology, University of Toronto, Ontario, Canada 2 Sleep Team, Center of Neuroscience of Lyon, UMR 5292 CNRS/U1028 INSERM, University of Lyon, Lyon, France 3 Center for Advanced Research in Sleep Medicine, Hoˆpital du Sacre´-Coeur de Montre´al, Universite´ de Montre´al Que´bec, Montre´al, QC Canada
During rapid eye movement (REM) sleep, skeletal muscles are almost paralyzed. However, in REM sleep behavior disorder (RBD), which is a rare neurological condition, muscle atonia is lost, leaving afflicted individuals free to enact their dreams. Although this may sound innocuous, it is not, given that patients with RBD often injure themselves or their bed-partner. A major concern in RBD is that it precedes, in 80% of cases, development of synucleinopathies, such as Parkinson’s disease (PD). This link suggests that neurodegenerative processes initially target the circuits controlling REM sleep. Clinical and basic neuroscience evidence indicates that RBD results from breakdown of the network underlying REM sleep atonia. This finding is important because it opens new avenues for treating RBD and understanding its link to neurodegenerative disorders. Introduction RBD is a parasomnia that is characterized by elaborate and often violent motor behaviors during REM sleep [1–4]. Motor behaviors in RBD can result in patient and/or bedpartner injury that often requires medical attention. RBD is a major public health concern because most patients eventually develop a neurodegenerative disease that is characterized by a-synuclein deposition [1,5]. More than 80% of patients with RBD eventually develop PD, multiple system atrophy (MSA), or dementia with Lewy bodies (DLB) [6]. At present, RBD is by far the strongest clinical predictor of onset of neurodegenerative diseases. The ability to identify prodromal neurodegeneration before actual disease onset has major scientific and clinical implications. Scientifically, RBD presents a unique opportunity to study the development of a neurodegenerative syndrome from its prodromal stages. Clinically, the study of RBD may be the ideal way to develop neuroprotective therapies for prevention of PD, MSA, and DLB [7]. Recent advances in the identification of the circuitry responsible for REM sleep atonia has made it possible to Corresponding author: Peever, J. ([email protected]). 0166-2236/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2014.02.009
determine potential RBD mechanisms [8,9]. For example, primary RBD symptoms are triggered in animal models when brainstem circuits controlling REM sleep are physically lesioned or genetically disturbed [10,11]. Additionally, recent brain-imaging studies and postmortem tissue analysis indicate that lesions encompassing the REM sleep circuit are associated with primary disease symptoms in patients with RBD [1,12,13]. Taken together, both clinical and basic science data suggest that RBD pathogenesis stems from breakdown in the brainstem circuits controlling REM sleep atonia. These new findings are important to the field of sleep medicine because they provide a mechanistic understanding of the identification, treatment, and prevention of RBD. They are also of relevance to understanding and treating synucleinopathies because they suggest that breakdown in REM circuitry could be used to predict, and thereby protect against, the onset of future neurodegeneration in patients with RBD [6]. Clinical features of RBD During normal REM sleep, movements are largely absent because skeletal muscles are effectively paralyzed [14,15]. However, in patients with RBD, this phenomenon is impaired and overt motor behaviors can occur [5]. Behaviors range from simple motor activities, such as talking, shouting, and limb jerking, to more complex movements that are seemingly purposeful and goal directed, such as gesturing, punching, or kicking. Motor behaviors are often violent in nature, which often results in injury of the patient and/or their bed-partner [16]. Injuries are the reason that patients initially seek medical consultation [3]. Nonviolent behaviors are also common and include culture-specific movements, such as gesturing [17]. There is a link between dream content and motor behaviors in RBD. Common dream content includes fighting off animals or unknown people, which may explain violent behaviors. Fear and anger are the most common emotions during dreams. Aggressive behaviors are prevalent and this contrasts with the typically mild-mannered temperament of patients during wakefulness [3,18]. Video-polysomnographic (PSG) recording is essential for RBD diagnosis. Excessive tonic or phasic chin electromyographic (EMG) activity or excessive limb EMG twitching during REM sleep is required for RBD diagnosis [19] (Figure 1). Other REM sleep features, including REM sleep Trends in Neurosciences xx (2014) 1–10
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Figure 1. Polysomnographic examples of normal rapid eye movement (REM) sleep and REM sleep of a patient with REM sleep behavior disorder (RBD). (A) A 30-s epoch of REM sleep in a control subject shows its three defining features: (i) rapid eye movements on the two electro-oculogram (EOG) leads; (ii) desynchronized electroencephalographic (EEG) activity on frontal, central, and occipital leads; and (iii) atonia on all electromyographic (EMG) leads (chin, legs, and arms). (B) A 30-s epoch of REM sleep in a patient with RBD exhibits the first two features of REM sleep. However, the chin, leg, and arm EMG leads show the excessive muscle activity that characterizes RBD.
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Review latency, total percentage of REM sleep time, and the number of REM sleep periods, are usually normal [20]. Periodic leg movements during sleep are also common in patients with RBD [21], but their expression differs from other conditions (e.g., restless legs syndrome) because leg movements are more prominent in REM sleep, less periodic in nature, and less responsive to dopaminergic treatments than in patients without RBD. Epidemiology The overall prevalence of RBD has been estimated to be 0.38–0.5% in the general population [22], but two recent population-based studies estimate that it may be as high as 2% after the age of 60 [23] and 6% after the age of 70 [24]. RBD predominantly affects males, but it may be underdiagnosed in females probably due to less violent REM sleep behaviours. A recent study found no clear difference in RBD prevalence between men and women with PD, but noted that females reported significantly fewer aggressive behaviors during REM sleep [25]. The genetic contribution to RBD remains largely unknown, but a questionnairebased study, revealed a positive family history of dream enactment behaviors for RBD (14%) compared with controls (5%) [2]. An association between RBD and human leukocyte antigen (HLA) class II genes has also been reported; 84% of Caucasian men with RDB (and without narcolepsy) were DQwl (DQB1*05, 06) positive compared with 56% in the control group [26]. Idiopathic and secondary RBD Idiopathic RBD (iRBD) is diagnosed when none of the conditions listed for secondary RBD (see below) or other conditions that mimic nocturnal manifestation of RBD, such as obstructive sleep apnea syndrome or nocturnal epilepsy, is present. Potential risk factors for iRBD have been identified, including smoking, head injury, pesticide exposure, and having worked as a farmer [27]. Secondary RBD is diagnosed when there is an associated condition that likely contributes to its etiology. By far the most prominent causes of secondary RBD are the neurodegenerative disorders characterized by intraneuronal deposition of a-synuclein (synucleinopathies), namely PD, MSA, and DLB [28,29]. Approximately half of patients with PD have RBD or REM sleep without atonia [7,30,31]. Interestingly, a video-monitored PSG study revealed that patients with PD show a striking improvement of their movements during RBD episodes compared with wakefulness [4]. There is also a strong association between RBD and DLB such that RBD is considered a supportive criterion for the diagnosis of DLB [32,33]. Finally, RBD is present in nearly all patients with MSA [34]. Secondary RBD may also be associated with intoxication or withdrawal from alcohol and other psychotropic substances and is common in long-term antidepressant usage [35]. Patients taking selective serotonin reuptake inhibitors are at increased risk of developing REM sleep without atonia, and perhaps also secondary RBD [36]. RBD is also common in narcolepsy [37]. However, in contrast to idiopathic RBD, narcolepsy-related RBD appears at a much younger age and may even appear during childhood [38]. PSG recordings show that 50% of
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narcoleptics have REM sleep without atonia [39]. Olfactory dysfunction is present in narcolepsy [40], but is less frequent and severe than in RBD [41], and is not associated with synucleinopathies. These observations suggest that narcoleptics with RBD display a distinct clinical entity compared with the idiopathic form of the disorder [42]. RBD can also be triggered by brainstem infarcts, tumors, and demyelinating lesions associated with multiple sclerosis [6,28]. The location of these lesions in the pontomedullary areas coincides with networks implicated in REM sleep control (see section on ‘Disease mechanisms in RBD’). RBD as a marker of neurodegeneration RBD often presents with concomitant conditions, especially neurodegenerative diseases, but even when it appears in its idiopathic form, RBD will often lead to neurodegenerative disease. The first observed link between iRBD and neurodegeneration came from a landmark paper by Schenck and colleagues [43] who found that 11 (38%) of their 29 original patients developed a synucleinopathy after 5 years. Subsequently, three prospective studies [7,44,45] found that patients with RBD have an elevated risk of developing PD and DLB. Recently, Schenck and coworkers [46] looked at the cohort they initially studied and found that 81% had developed parkinsonism or dementia after 16 years. The cohort studied by Iranzo et al. [7] was also recently revisited and 82% of the original participants had developed PD, DLB, MSA, or mild cognitive impairment [1]. A recent publication describing RBD onset more than 20 years before synucleinopathy suggests that preclinical synucleinopathy intervals are considerably longer than previously appreciated [47]. Given that most patients with RBD develop a synucleinopathy, they offer a unique opportunity to test markers of preclinical disease. Several markers of neurodegeneration were found in patients with iRBD. Subtle motor manifestations, usually bradykinesia, are frequent in iRBD [48] and quantitative motor tests allow detection of parkinsonism more than 4 years before the clinical diagnosis of PD [49]. Verbal and nonverbal learning, visuospatial constructional abilities, and attention and/or executive functions can be impaired in iRBD [50]. Olfactory loss, abnormalities in color discrimination [48,51], and autonomic dysfunction [52,53] occur early in iRBD, long before the development of synucleinopathies. Longitudinal follow-up showed that these abnormalities are present 5–10 years before disease onset, and they progress slowly during the preclinical stages [54]. Slowing of waking EEG activity (indexed by increased delta and theta frequencies and decreased alpha and beta frequencies [55,56]) and abnormalities in cerebral blood flow have been reported in RBD [57]. Similar changes have also been described during early stages of PD [58–62]. Other markers based on neuroimaging were also studied in iRBD. Single photon emission computerized tomography (SPECT) studies showed hypoperfusion in the frontal regions and hyperperfusion in the hippocampus [57,63]. Hyperperfusion in the hippocampus was more closely related to cognitive decline than to motor symptoms and, therefore, may specifically predict PD dementia or DLB. In addition, SPECT imaging showed that, compared with 3
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Review controls, patients had a significantly reduced dopamine transporter binding in the striatum and that a further decline in striatal tracer uptake was seen after 3 years, indicating a progressive deficit of nigrostriatal dopaminergic dysfunction [64]. In summary, RBD predisposes patients to the development of PD, DLB, or MSA, with a conversion rate of approximately 50% in 5 years and 80% after 15 years [1]. During this time, patients develop motor signs, altered cognitive abilities, decreased olfaction and color discrimination, and electroencephalogram (EEG) changes. These clinical markers, if present at the initial investigation, indicate a higher risk for patients with iRBD to develop a neurodegenerative syndrome at follow-up [44]. RBD treatment Given the strong association between RBD and PD, as well as findings of striatal dopamine dysfunction in patients with RBD, dopaminergic agents (especially pramipexole) have been used to treat RBD. However, this treatment strategy has had mixed success, with some studies reporting a therapeutic benefit [65,66], whereas others showed no clear improvement in RBD symptoms [67]. However, there is a general consensus that pramipexole does not function by reinstating REM sleep atonia or reducing phasic EMG activity during REM sleep [65–67]. Instead, pramipexole may act by changing actual dream content, given that one study reported a correlation between decreased frequency of RBD symptoms and decreased REM density [68]. Other medications have also been used for the symptomatic treatment of RBD [35,69], with clonazepam being considered the treatment of choice [69]. Substantial improvements have been reported in most patients treated with low doses [37]. This treatment strategy is effective over the long term (17 years), although some drug tolerance has been reported [70]. Clonazepam functions to suppress sleep behaviors, but does not restore normal REM sleep atonia [71]. The mechanism of action of clonazepam in RBD is unknown. Melatonin is also beneficial in treating idiopathic and secondary RBD [72]. Melatonin was originally used as an adjunct treatment to clonazepam [73], but in a recent open clinical trial, melatonin and clonazepam were each reported to reduce RBD motor behaviors and injuries in a comparable fashion [74]. Melatonin treatment partially restores REM sleep atonia, but has negligible effects on phasic motor activity [72]. It has been shown that melatonin potentiates the action of GABA on GABAA receptors located on motoneurons [11]. Therefore, melatonin could directly potentiate tonic GABAA transmission on the motoneurons that ultimately trigger REM sleep atonia. Mechanisms of REM sleep atonia Motor behaviors in RBD are associated with loss of REM sleep atonia; therefore, determining mechanisms mediating this natural motor phenomenon is pivotal to understanding RBD pathogenesis. Studies that have examined how skeletal motoneurons are controlled during REM sleep have elucidated the mechanisms of REM sleep atonia, and have provided clues about the upstream brain circuitry that ultimately triggers motor atonia. 4
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Intracellular recordings during REM sleep have shown that skeletal motoneurons are tonically hyperpolarized by large intracellular postsynaptic potentials [75]. In addition, local iontophoretic application of strychnine (glycine receptor antagonist) decreased motoneuron hyperpolarization, indicating that motoneurons are inhibited by a glycinergic mechanism during REM sleep [76]. Two series of functional studies further showed that GABA also contributes to motoneuron hyperpolarization in REM sleep. Biochemical data show that GABA and glycine are released onto motoneurons during drug-induced REM-like sleep [77], and pharmacological studies show that simultaneously antagonizing GABAA/GABAB/glycine receptors on motoneurons is necessary to prevent REM sleep atonia [14,15]. These data indicate that GABA- and glycine-mediated inhibition of motoneurons underlies REM sleep atonia. Therefore, loss of this normal inhibitory mechanism is a likely candidate in RBD pathogenesis (Figure 2). REM sleep atonia is not only triggered by motoneuron inhibition, but is also reinforced by reduced motoneuron excitation. Several studies show that multiple excitatory cell systems with inputs to motoneurons cease firing during REM sleep [78]. Loss or decrease of glutamatergic, noradrenergic, serotonergic, dopaminergic, and hypocretinergic activity during REM sleep may also function to reduce motoneuron activity excitation and thereby reinforce REM atonia [79–82]. Thus, it is possible that motor behaviors in RBD could be caused by an abnormal overactivation of these normally silent excitatory transmitter systems. Unit recording studies show that serotonin cells in the dorsal raphe fail to switch off during REM sleep in cats with experimentally induced RBD [83]. Identifying mechanisms controlling phasic motor activity during normal REM sleep (e.g., muscle twitches) is also important in understanding RBD, because exaggeration of such events could explain simple movements in RBD. Intracellular recording studies show that intermittent bursts of glutamatergic-driven motoneuron excitation cause muscle twitches during REM sleep [84], and functional studies show that blocking nonNMDA receptors on motoneurons prevents these twitches [80]. A functional GABA and glycine drive onto motoneurons normally acts to constrain the glutamate drive that triggers REM muscle twitches [14]. Pharmacological blockade of the GABA and glycine inhibitory drives increases motor twitches induced by glutamate during REM sleep [14,15], suggesting that excessive phasic movements in RBD results from the breakdown of normal GABA and glycine circuit function. REM sleep circuitry Identifying the circuitry controlling REM sleep is central to understanding RBD, because its breakdown likely underlies the disorder. The core circuits required for generating REM sleep are contained within the brainstem, but midbrain and forebrain circuits are also involved in its modulation [85,86]. A core component of REM sleep circuitry lies ventral and slightly rostral to the locus coeruleus at the caudal level of the laterodorsal tegmental cholinergic nucleus [9,87,88]. A variety of anatomical terms has been used to define this small pontine reticular region, including pontine inhibitory area, subcoeruleus nucleus, nucleus
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reticularis pontis oralis (dorsal division), peri-locus coeruleus alpha, and sublaterodorsal tegmental nucleus (Figure 2). In this review, we use the term ‘sublaterodorsal tegmental nucleus’ (SLD). SLD cells are ‘REM-ON’, meaning that they are more active during REM sleep than during nonREM sleep and waking [8,9,87,89,90]. The majority of these REM-ON cells synthesize glutamate (Figure 2) [91], and their drug-induced stimulation triggers motor atonia [9,92]. Conversely, small lesions placed bilaterally within the SLD result in loss of REM sleep atonia and subsequent RBD-like behaviors, but have negligible affects on REM sleep amounts. By contrast, larger lesions of the SLD not only prevent REM sleep atonia, but also affect the amount of REM sleep and the duration of REM sleep periods [9,87]. Together, these results suggest that REM sleep atonia and REM sleep itself are controlled by two distinct populations of SLD neurons. One population is responsible for triggering muscle atonia and the other for controlling REM sleep timing and inducing cortical activation during REM sleep (Figure 2). However, because REM sleep architecture is generally unaffected in RBD, this suggests that only the population of SLD cells controlling REM sleep atonia is affected in RBD. SLD cells induce REM atonia by recruiting inhibitory circuits localized in the ventromedial medulla [92–94]. REM-ON SLD cells are hypothesized to activate GABAand glycine-containing neurons in the ventral and alpha
gigantocellular reticular nucleus, which in turn trigger atonia by directly inhibiting skeletal motoneurons (Figure 2) [92,95]. However, there is also evidence suggesting that SLD cells induce REM atonia by activating inhibitory spinal interneurons, which in turn inactivate spinal motoneurons [87]. Although glutamatergic SLD neurons generate REM sleep atonia, they do not appear to induce the phasic motor events of REM sleep. The specific neuronal substrate responsible for generating phasic movements in REM sleep is unknown, but evidence indicates that the red nucleus, laterodorsal tegmental, and pedunculopontine nucleus are involved. Cells located in these nuclei discharge in synch with muscle twitches and other phasic REM events [96– 98]. Lesions or chemical manipulation of these regions interfere with the expression of phasic motor activity during REM sleep (e.g., pharmacological stimulation of the pedunculopontine nucleus increases phasic motor activity in REM sleep [99]). Activation of these pathways could explain some of the excessive movements of RBD. However, because movements in RBD are often highly coordinated and resemble voluntary movements during wakefulness (e.g., culture-specific gestures), this suggests that the motor cortex is also involved in driving movement in RBD. This idea is supported by the fact that pyramidal tract neurons, which mediate voluntary limb movement, are highly active during both wakefulness and REM sleep [100] (Figure 2).
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Figure 2. Circuitry responsible for motor control in rapid eye movement (REM) sleep and its potential involvement in REM sleep behavior disorder (RBD). During REM sleep, the descending REM-ON glutamatergic neurons of the sublaterodorsal tegmental nucleus (SLD) excite the REM-ON GABA- and glycine-releasing neurons in the ventral gigantocellular reticular nucleus (GiV). These GiV neurons project to and inhibit skeletal motoneurons, which causes REM sleep atonia. Another population of ascending SLD neurons induce activation of the cortex during REM sleep (including the motor cortex) by exciting intralaminar thalamocortical neurons. In healthy REM sleep, the SLD–GiV circuit inhibits motoneurons, which prevents pyramidal neurons in the motor cortex from producing movement. However, in patients with RBD, degeneration of the SLD–GiV circuit releases motoneurons from their normal source of inhibition, which allows excitatory projections from the motor cortex (via brainstem reticular neurons) to produce motor behaviors during REM sleep.
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Although the SLD is the core circuit required for triggering REM sleep and motor atonia, other circuits nonetheless function to modulate these behaviors. A comprehensive review by Brown et al. [101] documents some of this circuitry. Candidate brain structures include the ventrolateral periaqueductal gray, locus coeruleus, dorsal raphe, substantia nigra, lateral hypothalamus, amygdala, thalamus, and basal forebrain. Experimental manipulation of these regions is known to impact REM sleep behaviors, suggesting that their malfunction is linked to RBD symptoms [10,101]. In fact, pathology in some of these areas (e.g., locus coeruleus, dorsal raphe, substantia nigra, and lateral hypothalamus) has been reported in patients with RBD [28,102,103]. Models of RBD The pathophysiology of RBD has been markedly advanced by the development of animal models of the disorder. Lesions of the REM sleep-generating circuit can produce a motor syndrome reminiscent of RBD. For example, lesions of the SLD and medial medulla (including the gigantocellular reticular nucleus) can trigger a range of motor behaviors during otherwise normal REM sleep in adult cats, rats, and mice [3,87,93]. Importantly, such lesions also cause REM without atonia in infant rats [97,104], suggesting that REM-generating circuits are functional early during development. In adult rats, lesion-induced behaviors can range from simple loss of REM sleep atonia, to excessive muscle twitching, ataxic locomotion, and, in some cases, overt waking behaviors, such as mastication and grooming. However, the same lesions in adult cats produce a motor phenotype that is more reminiscent of motor behaviors in patients with RBD. For example, cats often engage in highly coordinated behaviors, such as walking, running, and even huntinglike behaviors [105]. It is important to realize that lesions of REM sleep-generating circuits (in both rodents and cats) primarily impact REM motor function, and have negligible effects on waking or nonREM sleep. These findings suggest that RBD could be caused by pathologies affecting the brainstem circuits that control REM sleep, and are important because they support clinical studies showing that degeneration of these same nuclei occurs in RBD patients (Figure 3) [1,12,13]. Lesions of the dopamine system have also been shown to produced RBD symptoms in monkeys [106], which is relevant to understanding disease pathogenesis because at least 35% of patients with RBD eventually develop PD
Panel 1: Brainstem circuits associated with REM sleep control exhibit abnormalies in RBD paents • Sublaterodorsal tegmental nucleus (subcoeruleus complex) • Gigantocellular recular nucleus • Dorsal raphe nucleus • Peduncoloponne nucleus TRENDS in Neurosciences
Figure 3. Brainstem regions that demonstrate neurodegeneration or some form of neuropathology in patients with rapid eye movement (REM) sleep behavior disorder (RBD).
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[30]. Recent data show that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced lesions of the dopamine system cause RBD symptoms. Verhave et al. [106] found that, immediately after MPTP treatment, monkeys experienced loss of REM motor atonia, despite having normal motor function during wakefulness (i.e., no PD symptoms). However, unlike lesions of the REM-generating circuits in cats and rodents, dopaminergic lesions did not produce overt movements during REM sleep. It remains to be confirmed if dopamine cell loss is responsible for loss of REM atonia in monkeys because MPTP also damages serotoninergic and noradrenergic cells. It is debatable whether dopaminergic system dysfunction underlies RBD because approximately 50% of patients with PD do not have RBD [30]. Nonetheless, this new study suggests that dopamine cell loss could be associated with RBD onset, which also supports imaging studies showing dopamine cell loss in patients with RBD [64]. Dysfunction of normal inhibitory neurotransmission has also been linked to RBD. Transgenic mice with reduced GABA and glycine receptor function develop the major symptoms of RBD, including behavioral, motor, and EEG phenotypes (Figure 4). It is not surprising that impaired inhibitory neurotransmission is associated with RBD behaviors, because REM sleep atonia is caused by GABA- and/or glycine-mediated inhibition of skeletal motoneurons [15], and damage to glycine- and/or GABA-rich brainstem regions can trigger an RBD-like syndrome [93,102,103]. Recently, Brooks and Peever found that transgenic mice with deficient glycine and GABAA receptor function exhibited the cardinal features of RBD [11] (Figure 4). For example, these mice exhibited overt motor behaviors (e.g., chewing and grooming) during REM sleep, and they experienced repeated muscle jerks and twitches during nonREM sleep, which are common in patients with RBD [3]. Transgenic mice also had moderate sleep disruption and marked EEG slowing, which can both occur in RBD [55] (Figure 4). Importantly, RBD symptoms were alleviated by clonazepam and melatonin, which are the most common and effective treatment for RBD symptoms. These findings are important because they are the first to link a potential genetic mechanism to RBD. Therefore, this model could be a useful resource for investigating in vivo disease mechanisms and developing potential therapeutics for RBD. These findings also emphasize the need to determine whether impairments in CNS inhibitory transmission contribute to human RBD. Disease mechanisms in RBD Brainstem lesions due to neurodegeneration, tumors, or ischemic injury can trigger RBD motor symptoms in some patients. Neuroimaging studies show that damage within or near the mesencephalic and pontine tegmental regions is associated with RBD symptoms [12,103,107–110]. It is important to realize that these regions broadly include the SLD and caudal ventromedial medulla that underlie generation of REM sleep atonia (Figure 2). In fact, a recent functional imaging study showed that magnitude of neuronal loss in the subcoeruleus strongly correlates with REM sleep without atonia in patients with RBD and comorbid PD, but not in patients with PD but without RBD
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Figure 4. Impaired inhibitory transmission triggers cardinal features of rapid eye movement (REM) sleep behavior disorder (RBD) in mice. (A) Electromyographic (EMG) and electroencephalographic (EEG) traces showing that, compared with wild type (Wt) mice, transgenic mice (Tg) exhibit elaborate motor activity during REM sleep. (B) EMG and EEG traces from a Wt and a Tg mouse showing that Tg mice experience brief, repetitive muscle twitches and/or jerks during nonREM sleep. (C) Hypnograms showing that, unlike Wt mice, Tg mice have markedly fragmented sleep, experiencing more transitions into and out of nonREM and REM sleep. (D) Waking EEG spectral profiles for Wt and Tg mice showing that Tg animals have more power in the lower frequency ranges and less power in the higher frequency ranges (i.e., EEG slowing). (E) Graphs showing that high levels of muscle tone in RBD mice are reduced by clonazepam and melatonin. Modified from [11].
[13]. This link suggests that loss of subcoeruleus neurons is the primary cause of REM motor behaviors in RBD. Postmortem studies of brain tissue from patients with RBD are also valuable resources for identifying potential disease mechanisms [1,6]. The most consistent and striking finding is the presence of Lewy bodies in the brainstem
structures associated with control of REM sleep atonia [33,110,111]. Lewy bodies, neuronal loss, depigmentation, and/or gliosis are located in (or near) the subcoeruleus, gigantocellular reticular nucleus, and pedunculopontine nucleus (Figure 3) [1,102,112–117]. These findings not only support neuroimaging data showing that neuronal cell loss 7
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Review in these areas is associated with RBD pathogenesis [12,13], but also substantiate basic neuroscience data showing that lesions positioned in these brainstem regions prevent REM sleep atonia [87,93–95]. Patients with RBD also exhibit changes in normal cholinergic system activity. Neuroimaging studies suggest that patients with both RBD and PD have significant degeneration of brain cholinergic systems, whereas, patients with PD but not RBD have normal cholinergic activity levels [118]. Given that a cholinergic mechanism functions to promote REM sleep atonia [119,120], it is possible that degeneration of brainstem cholinergic systems could underlie motor symptoms in patients with RBD and PD. Patients with RBD also experience pathological changes in basal ganglia anatomy. Neuroimaging studies show reduced striatal dopamine transporter expression and reduced striatal dopaminergic terminal densities in patients with RBD [64,116,117]. Pathological changes within the substantia nigra have also been reported in RBD [121]. A recent study found reduced striatal dopamine transporter expression in patients with RBD but without co-morbid PD symptoms, suggesting that dopamine dysfunction is associated with RBD [64]. The potential link between dopamine system dysfunction and RBD is also supported by findings showing a significant correlation between levels of REM sleep atonia and striatal dopaminergic terminal density in patients with RBD and MSA [122]. However, it is debatable whether the dopamine system has a direct role in RBD because only 30–60% of patients with PD exhibit RBD [4]. Instead, it is more likely that dopamine cell loss in RBD is associated with the pathological changes that underlie PD. It is well documented that neuronal damage begins in the lower brainstem before it progresses rostrally to affect the nigral circuits whose degeneration results in parkinsonian features [6]. It is important to realize that early degenerative processes in PD encompass the medullary and pontine circuits that control REM sleep atonia, which likely explains why RBD symptoms begin years before PD symptoms occur. However, because patients with RBD often exhibit mild cognitive impairment [44], this suggests that disease processes also impact rostral brain structures during early stages of RBD. Future directions Animal research has provided valuable insight into potential disease mechanisms in RBD [14,87]. Basic neuroscience studies have determined that REM sleep atonia is triggered by a two-part brainstem circuit (Figure 2) that, when experimentally lesioned, produces RBD symptoms in animals. Degeneration of this circuitry is associated with REM motor behaviors in RBD, suggesting that breakdown of REM sleep circuits underlies the disorder. Although initial studies suggest that REM atonia is triggered by SLD cells [91], their neurotransmitter phenotype remains ill defined. Future basic science studies need to focus on not only better characterization of REM generating circuits, but also understanding why such circuits are vulnerable to degeneration in RBD. RBD is more tightly linked to synucleinopathies than it is to tauopathies and other neurodegenerative disorders 8
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[6,7,28]. This correlation suggests that synucleinopathies impact the brainstem systems that control REM sleep, whereas tauopathies do not. Therefore, determining differences in brainstem physiology and anatomy between synucleinopathies and nonsynucleinopathies should provide a useful framework for identifying potential neural substrates of RBD. Identifying pathological changes in postmortem brainstem tissue from patients with RBD and concomitant synucleinopathies (e.g., PD) will help to establish a functional link between RBD and neurodegenerative processes. In idiopathic RBD, motor symptoms during REM sleep worsen with time [123], suggesting that progressive neuronal degeneration contributes to RBD symptoms. The possibility to study longitudinally prodromal markers years before disease onset has major scientific and clinical implications. It could help determine the sequence of cell loss in RBD and pinpoint the systems responsible for RBD onset and progression. Finding a way to identify those patients with RBD at even higher short-term risk of developing neurodegeneration will be important for the development of neuroprotective interventions. Clinical trials of this nature offer enormous potential in understanding the mechanistic underpinnings of RBD and their related neurodegenerative disorders. Acknowledgments J.P. was supported by research funding from NSERC and CIHR. J.M. was supported by research funds from CIHR. The authors thank Dominique Petit and Zoltan Torontali for their technical assistance.
References 1 Iranzo, A. et al. (2013) Neurodegenerative disease status and postmortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol. 12, 443–453 2 Dauvilliers, Y. et al. (2013) Family history of idiopathic REM behavior disorder: a multicenter case-control study. Neurology 80, 2233–2235 3 Schenck, C.H. and Mahowald, M.W. (2002) REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 25, 120–138 4 De Cock, V.C. et al. (2007) Restoration of normal motor control in Parkinson’s disease during REM sleep. Brain 130, 450–456 5 Schenck, C.H. and Mahowald, M.W. (1996) REM sleep parasomnias. Neurol. Clin. 14, 697–720 6 Boeve, B.F. (2013) Idiopathic REM sleep behaviour disorder in the development of Parkinson’s disease. Lancet Neurol. 12, 469–482 7 Iranzo, A. et al. (2006) Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol. 5, 572–577 8 Boissard, R. et al. (2003) Localization of the GABAergic and nonGABAergic neurons projecting to the sublaterodorsal nucleus and potentially gating paradoxical sleep onset. Eur. J. Neurosci. 18, 1627– 1639 9 Boissard, R. et al. (2002) The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study. Eur. J. Neurosci. 16, 1959–1973 10 Luppi, P.H. et al. (2011) The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder. Sleep Med. Rev. 15, 153–163 11 Brooks, P.L. and Peever, J.H. (2011) Impaired GABA and glycine transmission triggers cardinal features of rapid eye movement sleep behavior disorder in mice. J. Neurosci. 31, 7111–7121 12 Scherfler, C. et al. (2011) White and gray matter abnormalities in idiopathic rapid eye movement sleep behavior disorder: a diffusiontensor imaging and voxel-based morphometry study. Ann. Neurol. 69, 400–407
TINS-1044; No. of Pages 10
Review 13 Garcia-Lorenzo, D. et al. (2013) The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease. Brain 136, 2120–2129 14 Brooks, P.L. and Peever, J.H. (2008) Glycinergic and GABA(A)mediated inhibition of somatic motoneurons does not mediate rapid eye movement sleep motor atonia. J. Neurosci. 28, 3535–3545 15 Brooks, P.L. and Peever, J.H. (2012) Identification of the transmitter and receptor mechanisms responsible for REM sleep paralysis. J. Neurosci. 32, 9785–9795 16 Schenck, C.H. et al. (2009) Potentially lethal behaviors associated with rapid eye movement sleep behavior disorder: review of the literature and forensic implications. J. Forensic Sci. 54, 1475–1484 17 Oudiette, D. et al. (2009) Nonviolent elaborate behaviors may also occur in REM sleep behavior disorder. Neurology 72, 551–557 18 Fantini, M.L. et al. (2005) Aggressive dream content without daytime aggressiveness in REM sleep behavior disorder. Neurology 65, 1010– 1015 19 American Academy of Sleep Medicine (2005) International Classification Of Sleep Disorders 2, American Academy of Sleep Medicine 20 Frauscher, B. et al. (2012) Normative EMG values during REM sleep for the diagnosis of REM sleep behavior disorder. Sleep 35, 835–847 21 Fantini, M.L. et al. (2002) Periodic leg movements in REM sleep behavior disorder and related autonomic and EEG activation. Neurology 59, 1889–1894 22 Ohayon, M.M. et al. (1997) Violent behavior during sleep. J. Clin. Psychiatry 58, 369–376 quiz 377 23 Kang, S.H. et al. (2013) REM sleep behavior disorder in the Korean elderly population: prevalence and clinical characteristics. Sleep 36, 1147–1152 24 Boot, B.P. et al. (2012) Probable rapid eye movement sleep behavior disorder increases risk for mild cognitive impairment and Parkinson disease: a population-based study. Ann. Neurol. 71, 49–56 25 Bjornara, K.A. et al. (2013) REM sleep behavior disorder in Parkinson’s disease: is there a gender difference? Parkinsonism Relat. Disord. 19, 120–122 26 Schenck, C.H. et al. (1996) HLA class II genes associated with REM sleep behavior disorder. Ann. Neurol. 39, 261–263 27 Postuma, R.B. et al. (2012) Environmental risk factors for REM sleep behavior disorder: a multicenter case-control study. Neurology 79, 428–434 28 Gagnon, J.F. et al. (2006) Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases. Lancet Neurol. 5, 424–432 29 Manni, R. et al. (2011) Secondary ‘‘incidental’’ REM sleep behavior disorder: do we ever think of it? Sleep Med. 12 (Suppl. 2), S50–S53 30 Gagnon, J.F. et al. (2002) REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease. Neurology 59, 585–589 31 Sixel-Doring, F. et al. (2011) Associated factors for REM sleep behavior disorder in Parkinson disease. Neurology 77, 1048–1054 32 Ferman, T.J. et al. (2011) Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies. Neurology 77, 875–882 33 Boeve, B.F. et al. (1998) REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease. Neurology 51, 363–370 34 Iranzo, A. et al. (2005) Characteristics of idiopathic REM sleep behavior disorder and that associated with MSA and PD. Neurology 65, 247–252 35 Gagnon, J.F. et al. (2006) Update on the pharmacology of REM sleep behavior disorder. Neurology 67, 742–747 36 Winkelman, J.W. and James, L. (2004) Serotonergic antidepressants are associated with REM sleep without atonia. Sleep 27, 317–321 37 Olson, E.J. et al. (2000) Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 123, 331–339 38 Bonakis, A. et al. (2009) REM sleep behaviour disorder (RBD) and its associations in young patients. Sleep Med. 10, 641–645 39 Dauvilliers, Y. et al. (2007) REM sleep characteristics in narcolepsy and REM sleep behavior disorder. Sleep 30, 844–849 40 Buskova, J. et al. (2010) Olfactory dysfunction in narcolepsy with and without cataplexy. Sleep Med. 11, 558–561 41 Bayard, S. et al. (2010) Olfactory dysfunction in narcolepsy with cataplexy. Sleep Med. 11, 876–881 42 Oudiette, D. et al. (2012) A motor signature of REM sleep behavior disorder. Mov. Disord. 27, 428–431
Trends in Neurosciences xxx xxxx, Vol. xxx, No. x
43 Schenck, C.H. et al. (1996) Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 46, 388– 393 44 Postuma, R.B. et al. (2009) Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology 72, 1296–1300 45 Wing, Y.K. et al. (2012) Prospective outcome of rapid eye movement sleep behaviour disorder: psychiatric disorders as a potential early marker of Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 83, 470–472 46 Schenck, C.H. et al. (2013) Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med. 14, 744–748 47 Claassen, D.O. et al. (2010) REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology 75, 494–499 48 Postuma, R.B. et al. (2006) Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder. Neurology 66, 845–851 49 Postuma, R.B. et al. (2012) How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. Brain 135, 1860–1870 50 Massicotte-Marquez, J. et al. (2008) Executive dysfunction and memory impairment in idiopathic REM sleep behavior disorder. Neurology 70, 1250–1257 51 Fantini, M.L. et al. (2005) Idiopathic REM sleep behavior disorder: toward a better nosologic definition. Neurology 64, 780–786 52 Ferini-Strambi, L. et al. (1996) Cardiac autonomic activity during wakefulness and sleep in REM sleep behavior disorder. Sleep 19, 367– 369 53 Lanfranchi, P.A. et al. (2007) Cardiac autonomic regulation during sleep in idiopathic REM sleep behavior disorder. Sleep 30, 1019–1025 54 Postuma, R.B. et al. (2013) Prodromal autonomic symptoms and signs in Parkinson’s disease and dementia with Lewy bodies. Mov. Disord. 28, 597–604 55 Fantini, M.L. et al. (2003) Slowing of electroencephalogram in rapid eye movement sleep behavior disorder. Ann. Neurol. 53, 774–780 56 Iranzo, A. et al. (2010) Electroencephalographic slowing heralds mild cognitive impairment in idiopathic REM sleep behavior disorder. Sleep Med. 11, 534–539 57 Vendette, M. et al. (2011) Brain perfusion and markers of neurodegeneration in rapid eye movement sleep behavior disorder. Mov. Disord. 26, 1717–1724 58 Chaudhuri, K.R. (2001) Autonomic dysfunction in movement disorders. Curr. Opin. Neurol. 14, 505–511 59 Diederich, N.J. et al. (2002) Progressive worsening of spatial and chromatic processing deficits in Parkinson disease. Arch. Neurol. 59, 1249–1252 60 Katzenschlager, R. and Lees, A.J. (2004) Olfaction and Parkinson’s syndromes: its role in differential diagnosis. Curr. Opin. Neurol. 17, 417–423 61 Mosimann, U.P. et al. (2004) Visual perception in Parkinson disease dementia and dementia with Lewy bodies. Neurology 63, 2091–2096 62 Ponsen, M.M. et al. (2004) Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann. Neurol. 56, 173–181 63 Dang-Vu, T.T. et al. (2012) Hippocampal perfusion predicts impending neurodegeneration in REM sleep behavior disorder. Neurology 79, 2302–2306 64 Iranzo, A. et al. (2011) Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eyemovement sleep behaviour disorder: a prospective study. Lancet Neurol. 10, 797–805 65 Fantini, M.L. et al. (2003) The effects of pramipexole in REM sleep behavior disorder. Neurology 61, 1418–1420 66 Schmidt, M.H. et al. (2006) Use of pramipexole in REM sleep behavior disorder: results from a case series. Sleep Med. 7, 418–423 67 Kumru, H. et al. (2008) Lack of effects of pramipexole on REM sleep behavior disorder in Parkinson disease. Sleep 31, 1418–1421 68 Sasai, T. et al. (2012) Effectiveness of pramipexole, a dopamine agonist, on rapid eye movement sleep behavior disorder. Tohoku J. Exp. Med. 226, 177–181 9
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Review 69 Aurora, R.N. et al. (2010) Best practice guide for the treatment of REM sleep behavior disorder (RBD). J. Clin. Sleep Med. 6, 85–95 70 Mahowald, M.W. and Schenck, C.H. (2005) REM sleep parasomnias. In Principles and Practices of Sleep Medicine (Kryger, M.H. et al., eds), pp. 897–916, Saunders 71 Ferri, R. et al. (2013) Effects of long-term use of clonazepam on nonrapid eye movement sleep patterns in rapid eye movement sleep behavior disorder. Sleep Med. 14, 399–406 72 Kunz, D. and Mahlberg, R. (2010) A two-part, double-blind, placebocontrolled trial of exogenous melatonin in REM sleep behaviour disorder. J. Sleep Res. 19, 591–596 73 Boeve, B.F. et al. (2003) Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med. 4, 281–284 74 McCarter, S.J. et al. (2013) Treatment outcomes in REM sleep behavior disorder. Sleep Med. 14, 237–242 75 Nakamura, Y. et al. (1978) Intracellular analysis of trigeminal motoneuron activity during sleep in the cat. Science 199, 204–207 76 Soja, P.J. et al. (1991) The postsynaptic inhibitory control of lumbar motoneurons during the atonia of active sleep: effect of strychnine on motoneuron properties. J. Neurosci. 11, 2804–2811 77 Kodama, T. et al. (2003) Changes in inhibitory amino acid release linked to pontine-induced atonia: an in vivo microdialysis study. J. Neurosci. 23, 1548–1554 78 McGinty, D.J. and Harper, R.M. (1976) Dorsal raphe neurons: depression of firing during sleep in cats. Brain Res. 101, 569–575 79 Lai, Y.Y. et al. (2001) Changes in monoamine release in the ventral horn and hypoglossal nucleus linked to pontine inhibition of muscle tone: an in vivo microdialysis study. J. Neurosci. 21, 7384–7391 80 Burgess, C. et al. (2008) An endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone across the sleep-wake cycle. J. Neurosci. 28, 4649–4660 81 Chan, E. et al. (2006) Endogenous excitatory drive modulating respiratory muscle activity across sleep-wake states. Am. J. Respir. Crit. Care Med. 174, 1264–1273 82 Fenik, V.B. et al. (2005) REM sleep-like atonia of hypoglossal (XII) motoneurons is caused by loss of noradrenergic and serotonergic inputs. Am. J. Respir. Crit. Care Med. 172, 1322–1330 83 Trulson, M.E. et al. (1981) Raphe unit activity during REM sleep in normal cats and in pontine lesioned cats displaying REM sleep without atonia. Brain Res. 226, 75–91 84 Soja, P.J. et al. (1995) Effects of excitatory amino acid antagonists on the phasic depolarizing events that occur in lumbar motoneurons during REM periods of active sleep. J. Neurosci. 15, 4068–4076 85 Siegel, J.M. et al. (1986) Behavioral states in the chronic medullary and midpontine cat. Electroencephalogr. Clin. Neurophysiol. 63, 274–288 86 Luppi, P.H. et al. (2013) Paradoxical (REM) sleep genesis by the brainstem is under hypothalamic control. Curr. Opin. Neurobiol. 23, 786–792 87 Lu, J. et al. (2006) A putative flip-flop switch for control of REM sleep. Nature 441, 589–594 88 Baghdoyan, H.A. et al. (1984) Site-specific enhancement and suppression of desynchronized sleep signs following cholinergic stimulation of three brainstem regions. Brain Res. 306, 39–52 89 Siegel, J.M. et al. (1991) Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla. Science 252, 1315–1318 90 Maloney, K.J. et al. (1999) Differential c-Fos expression in cholinergic, monoaminergic, and GABAergic cell groups of the pontomesencephalic tegmentum after paradoxical sleep deprivation and recovery. J. Neurosci. 19, 3057–3072 91 Clement, O. et al. (2011) Evidence that neurons of the sublaterodorsal tegmental nucleus triggering paradoxical (REM) sleep are glutamatergic. Sleep 34, 419–423 92 Lai, Y.Y. and Siegel, J.M. (1988) Medullary regions mediating atonia. J. Neurosci. 8, 4790–4796 93 Schenkel, E. and Siegel, J.M. (1989) REM-sleep without atonia after lesions of the medial medulla. Neurosci. Lett. 98, 159–165 94 Holmes, C.J. et al. (1994) Distribution of cholinergic, GABAergic and serotonergic neurons in the medial medullary reticular formation and their projections studied by cytotoxic lesions in the cat. Neuroscience 62, 1155–1178 95 Vetrivelan, R. et al. (2009) Medullary circuitry regulating rapid eye movement sleep and motor atonia. J. Neurosci. 29, 9361–9369 10
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96 Lim, A.S. et al. (2007) Characterization of REM-sleep associated ponto-geniculo-occipital waves in the human pons. Sleep 30, 823–827 97 Karlsson, K.A. et al. (2005) The neural substrates of infant sleep in rats. PLoS Biol. 3, e143 98 Gassel, M.M. et al. (1966) Rubrospinal influences during desynchronized sleep. Nature 209, 1218–1220 99 Grace, K.P. et al. (2012) 5-HT1A receptor-responsive pedunculopontine tegmental neurons suppress REM sleep and respiratory motor activity. J. Neurosci. 32, 1622–1633 100 Evarts, E.V. (1964) Temporal patterns of discharge of pyramidal tract neurons during sleep and waking in the monkey. J. Neurophysiol. 27, 152–171 101 Brown, R.E. et al. (2012) Control of sleep and wakefulness. Physiol. Rev. 92, 1087–1187 102 Boeve, B.F. et al. (2007) Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 130, 2770–2788 103 Mathis, J. et al. (2007) Isolated mediotegmental lesion causing narcolepsy and rapid eye movement sleep behaviour disorder: a case evidencing a common pathway in narcolepsy and rapid eye movement sleep behaviour disorder. J. Neurol. Neurosurg. Psychiatry 78, 427–429 104 Karlsson, K.A. and Blumberg, M.S. (2005) Active medullary control of atonia in week-old rats. Neuroscience 130, 275–283 105 Jouvet, M. (1962) Recherches sur les structures nerveuses et les mecanismes responsables des differentes phases du sommeil physiologique. Arch. Ital. Biol. 100, 125–206 106 Verhave, P.S. et al. (2011) REM sleep behavior disorder in the marmoset MPTP model of early Parkinson disease. Sleep 34, 1119– 1125 107 Provini, F. et al. (2004) Status dissociatus after surgery for tegmental ponto-mesencephalic cavernoma: a state-dependent disorder of motor control during sleep. Mov. Disord. 19, 719–723 108 Tippmann-Peikert, M. et al. (2006) REM sleep behavior disorder initiated by acute brainstem multiple sclerosis. Neurology 66, 1277–1279 109 Plazzi, G. and Montagna, P. (2002) Remitting REM sleep behavior disorder as the initial sign of multiple sclerosis. Sleep Med. 3, 437–439 110 Schenck, C.H. et al. (1996) A case of REM sleep behavior disorder with autopsy-confirmed Alzheimer’s disease: postmortem brain stem histochemical analyses. Biol. Psychiatry 40, 422–425 111 Uchiyama, M. et al. (1995) Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology 45, 709–712 112 Benarroch, E.E. (2002) New findings on the neuropathology of multiple system atrophy. Auton. Neurosci. 96, 59–62 113 Turner, R.S. et al. (2000) The pathology of REM sleep behavior disorder with comorbid Lewy body dementia. Neurology 55, 1730–1732 114 Schenck, C.H. et al. (1997) Lewy body variant of Alzheimer’s disease (AD) identified by postmortem ubiquitin staining in a previously reported case of AD associated with REM sleep behavior disorder. Biol. Psychiatry 42, 527–528 115 Boeve, B. et al. (2003) Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 61, 40– 45 116 Albin, R.L. et al. (2000) Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurology 55, 1410–1412 117 Eisensehr, I. et al. (2000) Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder - Comparison with Parkinson’s disease and controls. Brain 123, 1155–1160 118 Kotagal, V. et al. (2012) Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease. Ann. Neurol. 71, 560–568 119 Grace, K.P. et al. (2012) Identification of the mechanism mediating genioglossus muscle suppression in REM sleep. Am. J. Respir. Crit. Care Med. 187, 311–319 120 Torontali, Z. et al. (2014) Cholinergic involvement in control of REM sleep paralysis. J. Physiol. (in press) 121 Miyamoto, M. et al. (2012) Preclinical substantia nigra dysfunction in rapid eye movement sleep behaviour disorder. Sleep Med. 13, 102–106 122 Gilman, S. et al. (2003) REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA. Neurology 61, 29–34 123 Iranzo, A. et al. (2009) Excessive muscle activity increases over time in idiopathic REM sleep behavior disorder. Sleep 32, 1149–1153
Review
Breakdown in REM sleep circuitry underlies REM sleep behavior disorder John Peever1, Pierre-Herve´ Luppi2, and Jacques Montplaisir3 1
Systems Neurobiology Laboratory, Departments of Cell and Systems Biology and Physiology, University of Toronto, Ontario, Canada 2 Sleep Team, Center of Neuroscience of Lyon, UMR 5292 CNRS/U1028 INSERM, University of Lyon, Lyon, France 3 Center for Advanced Research in Sleep Medicine, Hoˆpital du Sacre´-Coeur de Montre´al, Universite´ de Montre´al Que´bec, Montre´al, QC Canada
During rapid eye movement (REM) sleep, skeletal muscles are almost paralyzed. However, in REM sleep behavior disorder (RBD), which is a rare neurological condition, muscle atonia is lost, leaving afflicted individuals free to enact their dreams. Although this may sound innocuous, it is not, given that patients with RBD often injure themselves or their bed-partner. A major concern in RBD is that it precedes, in 80% of cases, development of synucleinopathies, such as Parkinson’s disease (PD). This link suggests that neurodegenerative processes initially target the circuits controlling REM sleep. Clinical and basic neuroscience evidence indicates that RBD results from breakdown of the network underlying REM sleep atonia. This finding is important because it opens new avenues for treating RBD and understanding its link to neurodegenerative disorders. Introduction RBD is a parasomnia that is characterized by elaborate and often violent motor behaviors during REM sleep [1–4]. Motor behaviors in RBD can result in patient and/or bedpartner injury that often requires medical attention. RBD is a major public health concern because most patients eventually develop a neurodegenerative disease that is characterized by a-synuclein deposition [1,5]. More than 80% of patients with RBD eventually develop PD, multiple system atrophy (MSA), or dementia with Lewy bodies (DLB) [6]. At present, RBD is by far the strongest clinical predictor of onset of neurodegenerative diseases. The ability to identify prodromal neurodegeneration before actual disease onset has major scientific and clinical implications. Scientifically, RBD presents a unique opportunity to study the development of a neurodegenerative syndrome from its prodromal stages. Clinically, the study of RBD may be the ideal way to develop neuroprotective therapies for prevention of PD, MSA, and DLB [7]. Recent advances in the identification of the circuitry responsible for REM sleep atonia has made it possible to Corresponding author: Peever, J. ([email protected]). 0166-2236/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2014.02.009
determine potential RBD mechanisms [8,9]. For example, primary RBD symptoms are triggered in animal models when brainstem circuits controlling REM sleep are physically lesioned or genetically disturbed [10,11]. Additionally, recent brain-imaging studies and postmortem tissue analysis indicate that lesions encompassing the REM sleep circuit are associated with primary disease symptoms in patients with RBD [1,12,13]. Taken together, both clinical and basic science data suggest that RBD pathogenesis stems from breakdown in the brainstem circuits controlling REM sleep atonia. These new findings are important to the field of sleep medicine because they provide a mechanistic understanding of the identification, treatment, and prevention of RBD. They are also of relevance to understanding and treating synucleinopathies because they suggest that breakdown in REM circuitry could be used to predict, and thereby protect against, the onset of future neurodegeneration in patients with RBD [6]. Clinical features of RBD During normal REM sleep, movements are largely absent because skeletal muscles are effectively paralyzed [14,15]. However, in patients with RBD, this phenomenon is impaired and overt motor behaviors can occur [5]. Behaviors range from simple motor activities, such as talking, shouting, and limb jerking, to more complex movements that are seemingly purposeful and goal directed, such as gesturing, punching, or kicking. Motor behaviors are often violent in nature, which often results in injury of the patient and/or their bed-partner [16]. Injuries are the reason that patients initially seek medical consultation [3]. Nonviolent behaviors are also common and include culture-specific movements, such as gesturing [17]. There is a link between dream content and motor behaviors in RBD. Common dream content includes fighting off animals or unknown people, which may explain violent behaviors. Fear and anger are the most common emotions during dreams. Aggressive behaviors are prevalent and this contrasts with the typically mild-mannered temperament of patients during wakefulness [3,18]. Video-polysomnographic (PSG) recording is essential for RBD diagnosis. Excessive tonic or phasic chin electromyographic (EMG) activity or excessive limb EMG twitching during REM sleep is required for RBD diagnosis [19] (Figure 1). Other REM sleep features, including REM sleep Trends in Neurosciences xx (2014) 1–10
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(A) Le EOG
Right EOG
Chin EMG
Frontal EEG
Central EEG
Occipital EEG Le leg EMG
Right leg EMG
Le arm EMG
Right arm EMG
(B) Le EOG
Right EOG
Chin EMG
Frontal EEG
Central EEG
Occipital EEG Le leg EMG
Right leg EMG
Le arm EMG
Right arm EMG
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Figure 1. Polysomnographic examples of normal rapid eye movement (REM) sleep and REM sleep of a patient with REM sleep behavior disorder (RBD). (A) A 30-s epoch of REM sleep in a control subject shows its three defining features: (i) rapid eye movements on the two electro-oculogram (EOG) leads; (ii) desynchronized electroencephalographic (EEG) activity on frontal, central, and occipital leads; and (iii) atonia on all electromyographic (EMG) leads (chin, legs, and arms). (B) A 30-s epoch of REM sleep in a patient with RBD exhibits the first two features of REM sleep. However, the chin, leg, and arm EMG leads show the excessive muscle activity that characterizes RBD.
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Review latency, total percentage of REM sleep time, and the number of REM sleep periods, are usually normal [20]. Periodic leg movements during sleep are also common in patients with RBD [21], but their expression differs from other conditions (e.g., restless legs syndrome) because leg movements are more prominent in REM sleep, less periodic in nature, and less responsive to dopaminergic treatments than in patients without RBD. Epidemiology The overall prevalence of RBD has been estimated to be 0.38–0.5% in the general population [22], but two recent population-based studies estimate that it may be as high as 2% after the age of 60 [23] and 6% after the age of 70 [24]. RBD predominantly affects males, but it may be underdiagnosed in females probably due to less violent REM sleep behaviours. A recent study found no clear difference in RBD prevalence between men and women with PD, but noted that females reported significantly fewer aggressive behaviors during REM sleep [25]. The genetic contribution to RBD remains largely unknown, but a questionnairebased study, revealed a positive family history of dream enactment behaviors for RBD (14%) compared with controls (5%) [2]. An association between RBD and human leukocyte antigen (HLA) class II genes has also been reported; 84% of Caucasian men with RDB (and without narcolepsy) were DQwl (DQB1*05, 06) positive compared with 56% in the control group [26]. Idiopathic and secondary RBD Idiopathic RBD (iRBD) is diagnosed when none of the conditions listed for secondary RBD (see below) or other conditions that mimic nocturnal manifestation of RBD, such as obstructive sleep apnea syndrome or nocturnal epilepsy, is present. Potential risk factors for iRBD have been identified, including smoking, head injury, pesticide exposure, and having worked as a farmer [27]. Secondary RBD is diagnosed when there is an associated condition that likely contributes to its etiology. By far the most prominent causes of secondary RBD are the neurodegenerative disorders characterized by intraneuronal deposition of a-synuclein (synucleinopathies), namely PD, MSA, and DLB [28,29]. Approximately half of patients with PD have RBD or REM sleep without atonia [7,30,31]. Interestingly, a video-monitored PSG study revealed that patients with PD show a striking improvement of their movements during RBD episodes compared with wakefulness [4]. There is also a strong association between RBD and DLB such that RBD is considered a supportive criterion for the diagnosis of DLB [32,33]. Finally, RBD is present in nearly all patients with MSA [34]. Secondary RBD may also be associated with intoxication or withdrawal from alcohol and other psychotropic substances and is common in long-term antidepressant usage [35]. Patients taking selective serotonin reuptake inhibitors are at increased risk of developing REM sleep without atonia, and perhaps also secondary RBD [36]. RBD is also common in narcolepsy [37]. However, in contrast to idiopathic RBD, narcolepsy-related RBD appears at a much younger age and may even appear during childhood [38]. PSG recordings show that 50% of
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narcoleptics have REM sleep without atonia [39]. Olfactory dysfunction is present in narcolepsy [40], but is less frequent and severe than in RBD [41], and is not associated with synucleinopathies. These observations suggest that narcoleptics with RBD display a distinct clinical entity compared with the idiopathic form of the disorder [42]. RBD can also be triggered by brainstem infarcts, tumors, and demyelinating lesions associated with multiple sclerosis [6,28]. The location of these lesions in the pontomedullary areas coincides with networks implicated in REM sleep control (see section on ‘Disease mechanisms in RBD’). RBD as a marker of neurodegeneration RBD often presents with concomitant conditions, especially neurodegenerative diseases, but even when it appears in its idiopathic form, RBD will often lead to neurodegenerative disease. The first observed link between iRBD and neurodegeneration came from a landmark paper by Schenck and colleagues [43] who found that 11 (38%) of their 29 original patients developed a synucleinopathy after 5 years. Subsequently, three prospective studies [7,44,45] found that patients with RBD have an elevated risk of developing PD and DLB. Recently, Schenck and coworkers [46] looked at the cohort they initially studied and found that 81% had developed parkinsonism or dementia after 16 years. The cohort studied by Iranzo et al. [7] was also recently revisited and 82% of the original participants had developed PD, DLB, MSA, or mild cognitive impairment [1]. A recent publication describing RBD onset more than 20 years before synucleinopathy suggests that preclinical synucleinopathy intervals are considerably longer than previously appreciated [47]. Given that most patients with RBD develop a synucleinopathy, they offer a unique opportunity to test markers of preclinical disease. Several markers of neurodegeneration were found in patients with iRBD. Subtle motor manifestations, usually bradykinesia, are frequent in iRBD [48] and quantitative motor tests allow detection of parkinsonism more than 4 years before the clinical diagnosis of PD [49]. Verbal and nonverbal learning, visuospatial constructional abilities, and attention and/or executive functions can be impaired in iRBD [50]. Olfactory loss, abnormalities in color discrimination [48,51], and autonomic dysfunction [52,53] occur early in iRBD, long before the development of synucleinopathies. Longitudinal follow-up showed that these abnormalities are present 5–10 years before disease onset, and they progress slowly during the preclinical stages [54]. Slowing of waking EEG activity (indexed by increased delta and theta frequencies and decreased alpha and beta frequencies [55,56]) and abnormalities in cerebral blood flow have been reported in RBD [57]. Similar changes have also been described during early stages of PD [58–62]. Other markers based on neuroimaging were also studied in iRBD. Single photon emission computerized tomography (SPECT) studies showed hypoperfusion in the frontal regions and hyperperfusion in the hippocampus [57,63]. Hyperperfusion in the hippocampus was more closely related to cognitive decline than to motor symptoms and, therefore, may specifically predict PD dementia or DLB. In addition, SPECT imaging showed that, compared with 3
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Review controls, patients had a significantly reduced dopamine transporter binding in the striatum and that a further decline in striatal tracer uptake was seen after 3 years, indicating a progressive deficit of nigrostriatal dopaminergic dysfunction [64]. In summary, RBD predisposes patients to the development of PD, DLB, or MSA, with a conversion rate of approximately 50% in 5 years and 80% after 15 years [1]. During this time, patients develop motor signs, altered cognitive abilities, decreased olfaction and color discrimination, and electroencephalogram (EEG) changes. These clinical markers, if present at the initial investigation, indicate a higher risk for patients with iRBD to develop a neurodegenerative syndrome at follow-up [44]. RBD treatment Given the strong association between RBD and PD, as well as findings of striatal dopamine dysfunction in patients with RBD, dopaminergic agents (especially pramipexole) have been used to treat RBD. However, this treatment strategy has had mixed success, with some studies reporting a therapeutic benefit [65,66], whereas others showed no clear improvement in RBD symptoms [67]. However, there is a general consensus that pramipexole does not function by reinstating REM sleep atonia or reducing phasic EMG activity during REM sleep [65–67]. Instead, pramipexole may act by changing actual dream content, given that one study reported a correlation between decreased frequency of RBD symptoms and decreased REM density [68]. Other medications have also been used for the symptomatic treatment of RBD [35,69], with clonazepam being considered the treatment of choice [69]. Substantial improvements have been reported in most patients treated with low doses [37]. This treatment strategy is effective over the long term (17 years), although some drug tolerance has been reported [70]. Clonazepam functions to suppress sleep behaviors, but does not restore normal REM sleep atonia [71]. The mechanism of action of clonazepam in RBD is unknown. Melatonin is also beneficial in treating idiopathic and secondary RBD [72]. Melatonin was originally used as an adjunct treatment to clonazepam [73], but in a recent open clinical trial, melatonin and clonazepam were each reported to reduce RBD motor behaviors and injuries in a comparable fashion [74]. Melatonin treatment partially restores REM sleep atonia, but has negligible effects on phasic motor activity [72]. It has been shown that melatonin potentiates the action of GABA on GABAA receptors located on motoneurons [11]. Therefore, melatonin could directly potentiate tonic GABAA transmission on the motoneurons that ultimately trigger REM sleep atonia. Mechanisms of REM sleep atonia Motor behaviors in RBD are associated with loss of REM sleep atonia; therefore, determining mechanisms mediating this natural motor phenomenon is pivotal to understanding RBD pathogenesis. Studies that have examined how skeletal motoneurons are controlled during REM sleep have elucidated the mechanisms of REM sleep atonia, and have provided clues about the upstream brain circuitry that ultimately triggers motor atonia. 4
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Intracellular recordings during REM sleep have shown that skeletal motoneurons are tonically hyperpolarized by large intracellular postsynaptic potentials [75]. In addition, local iontophoretic application of strychnine (glycine receptor antagonist) decreased motoneuron hyperpolarization, indicating that motoneurons are inhibited by a glycinergic mechanism during REM sleep [76]. Two series of functional studies further showed that GABA also contributes to motoneuron hyperpolarization in REM sleep. Biochemical data show that GABA and glycine are released onto motoneurons during drug-induced REM-like sleep [77], and pharmacological studies show that simultaneously antagonizing GABAA/GABAB/glycine receptors on motoneurons is necessary to prevent REM sleep atonia [14,15]. These data indicate that GABA- and glycine-mediated inhibition of motoneurons underlies REM sleep atonia. Therefore, loss of this normal inhibitory mechanism is a likely candidate in RBD pathogenesis (Figure 2). REM sleep atonia is not only triggered by motoneuron inhibition, but is also reinforced by reduced motoneuron excitation. Several studies show that multiple excitatory cell systems with inputs to motoneurons cease firing during REM sleep [78]. Loss or decrease of glutamatergic, noradrenergic, serotonergic, dopaminergic, and hypocretinergic activity during REM sleep may also function to reduce motoneuron activity excitation and thereby reinforce REM atonia [79–82]. Thus, it is possible that motor behaviors in RBD could be caused by an abnormal overactivation of these normally silent excitatory transmitter systems. Unit recording studies show that serotonin cells in the dorsal raphe fail to switch off during REM sleep in cats with experimentally induced RBD [83]. Identifying mechanisms controlling phasic motor activity during normal REM sleep (e.g., muscle twitches) is also important in understanding RBD, because exaggeration of such events could explain simple movements in RBD. Intracellular recording studies show that intermittent bursts of glutamatergic-driven motoneuron excitation cause muscle twitches during REM sleep [84], and functional studies show that blocking nonNMDA receptors on motoneurons prevents these twitches [80]. A functional GABA and glycine drive onto motoneurons normally acts to constrain the glutamate drive that triggers REM muscle twitches [14]. Pharmacological blockade of the GABA and glycine inhibitory drives increases motor twitches induced by glutamate during REM sleep [14,15], suggesting that excessive phasic movements in RBD results from the breakdown of normal GABA and glycine circuit function. REM sleep circuitry Identifying the circuitry controlling REM sleep is central to understanding RBD, because its breakdown likely underlies the disorder. The core circuits required for generating REM sleep are contained within the brainstem, but midbrain and forebrain circuits are also involved in its modulation [85,86]. A core component of REM sleep circuitry lies ventral and slightly rostral to the locus coeruleus at the caudal level of the laterodorsal tegmental cholinergic nucleus [9,87,88]. A variety of anatomical terms has been used to define this small pontine reticular region, including pontine inhibitory area, subcoeruleus nucleus, nucleus
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reticularis pontis oralis (dorsal division), peri-locus coeruleus alpha, and sublaterodorsal tegmental nucleus (Figure 2). In this review, we use the term ‘sublaterodorsal tegmental nucleus’ (SLD). SLD cells are ‘REM-ON’, meaning that they are more active during REM sleep than during nonREM sleep and waking [8,9,87,89,90]. The majority of these REM-ON cells synthesize glutamate (Figure 2) [91], and their drug-induced stimulation triggers motor atonia [9,92]. Conversely, small lesions placed bilaterally within the SLD result in loss of REM sleep atonia and subsequent RBD-like behaviors, but have negligible affects on REM sleep amounts. By contrast, larger lesions of the SLD not only prevent REM sleep atonia, but also affect the amount of REM sleep and the duration of REM sleep periods [9,87]. Together, these results suggest that REM sleep atonia and REM sleep itself are controlled by two distinct populations of SLD neurons. One population is responsible for triggering muscle atonia and the other for controlling REM sleep timing and inducing cortical activation during REM sleep (Figure 2). However, because REM sleep architecture is generally unaffected in RBD, this suggests that only the population of SLD cells controlling REM sleep atonia is affected in RBD. SLD cells induce REM atonia by recruiting inhibitory circuits localized in the ventromedial medulla [92–94]. REM-ON SLD cells are hypothesized to activate GABAand glycine-containing neurons in the ventral and alpha
gigantocellular reticular nucleus, which in turn trigger atonia by directly inhibiting skeletal motoneurons (Figure 2) [92,95]. However, there is also evidence suggesting that SLD cells induce REM atonia by activating inhibitory spinal interneurons, which in turn inactivate spinal motoneurons [87]. Although glutamatergic SLD neurons generate REM sleep atonia, they do not appear to induce the phasic motor events of REM sleep. The specific neuronal substrate responsible for generating phasic movements in REM sleep is unknown, but evidence indicates that the red nucleus, laterodorsal tegmental, and pedunculopontine nucleus are involved. Cells located in these nuclei discharge in synch with muscle twitches and other phasic REM events [96– 98]. Lesions or chemical manipulation of these regions interfere with the expression of phasic motor activity during REM sleep (e.g., pharmacological stimulation of the pedunculopontine nucleus increases phasic motor activity in REM sleep [99]). Activation of these pathways could explain some of the excessive movements of RBD. However, because movements in RBD are often highly coordinated and resemble voluntary movements during wakefulness (e.g., culture-specific gestures), this suggests that the motor cortex is also involved in driving movement in RBD. This idea is supported by the fact that pyramidal tract neurons, which mediate voluntary limb movement, are highly active during both wakefulness and REM sleep [100] (Figure 2).
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Figure 2. Circuitry responsible for motor control in rapid eye movement (REM) sleep and its potential involvement in REM sleep behavior disorder (RBD). During REM sleep, the descending REM-ON glutamatergic neurons of the sublaterodorsal tegmental nucleus (SLD) excite the REM-ON GABA- and glycine-releasing neurons in the ventral gigantocellular reticular nucleus (GiV). These GiV neurons project to and inhibit skeletal motoneurons, which causes REM sleep atonia. Another population of ascending SLD neurons induce activation of the cortex during REM sleep (including the motor cortex) by exciting intralaminar thalamocortical neurons. In healthy REM sleep, the SLD–GiV circuit inhibits motoneurons, which prevents pyramidal neurons in the motor cortex from producing movement. However, in patients with RBD, degeneration of the SLD–GiV circuit releases motoneurons from their normal source of inhibition, which allows excitatory projections from the motor cortex (via brainstem reticular neurons) to produce motor behaviors during REM sleep.
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Although the SLD is the core circuit required for triggering REM sleep and motor atonia, other circuits nonetheless function to modulate these behaviors. A comprehensive review by Brown et al. [101] documents some of this circuitry. Candidate brain structures include the ventrolateral periaqueductal gray, locus coeruleus, dorsal raphe, substantia nigra, lateral hypothalamus, amygdala, thalamus, and basal forebrain. Experimental manipulation of these regions is known to impact REM sleep behaviors, suggesting that their malfunction is linked to RBD symptoms [10,101]. In fact, pathology in some of these areas (e.g., locus coeruleus, dorsal raphe, substantia nigra, and lateral hypothalamus) has been reported in patients with RBD [28,102,103]. Models of RBD The pathophysiology of RBD has been markedly advanced by the development of animal models of the disorder. Lesions of the REM sleep-generating circuit can produce a motor syndrome reminiscent of RBD. For example, lesions of the SLD and medial medulla (including the gigantocellular reticular nucleus) can trigger a range of motor behaviors during otherwise normal REM sleep in adult cats, rats, and mice [3,87,93]. Importantly, such lesions also cause REM without atonia in infant rats [97,104], suggesting that REM-generating circuits are functional early during development. In adult rats, lesion-induced behaviors can range from simple loss of REM sleep atonia, to excessive muscle twitching, ataxic locomotion, and, in some cases, overt waking behaviors, such as mastication and grooming. However, the same lesions in adult cats produce a motor phenotype that is more reminiscent of motor behaviors in patients with RBD. For example, cats often engage in highly coordinated behaviors, such as walking, running, and even huntinglike behaviors [105]. It is important to realize that lesions of REM sleep-generating circuits (in both rodents and cats) primarily impact REM motor function, and have negligible effects on waking or nonREM sleep. These findings suggest that RBD could be caused by pathologies affecting the brainstem circuits that control REM sleep, and are important because they support clinical studies showing that degeneration of these same nuclei occurs in RBD patients (Figure 3) [1,12,13]. Lesions of the dopamine system have also been shown to produced RBD symptoms in monkeys [106], which is relevant to understanding disease pathogenesis because at least 35% of patients with RBD eventually develop PD
Panel 1: Brainstem circuits associated with REM sleep control exhibit abnormalies in RBD paents • Sublaterodorsal tegmental nucleus (subcoeruleus complex) • Gigantocellular recular nucleus • Dorsal raphe nucleus • Peduncoloponne nucleus TRENDS in Neurosciences
Figure 3. Brainstem regions that demonstrate neurodegeneration or some form of neuropathology in patients with rapid eye movement (REM) sleep behavior disorder (RBD).
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[30]. Recent data show that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced lesions of the dopamine system cause RBD symptoms. Verhave et al. [106] found that, immediately after MPTP treatment, monkeys experienced loss of REM motor atonia, despite having normal motor function during wakefulness (i.e., no PD symptoms). However, unlike lesions of the REM-generating circuits in cats and rodents, dopaminergic lesions did not produce overt movements during REM sleep. It remains to be confirmed if dopamine cell loss is responsible for loss of REM atonia in monkeys because MPTP also damages serotoninergic and noradrenergic cells. It is debatable whether dopaminergic system dysfunction underlies RBD because approximately 50% of patients with PD do not have RBD [30]. Nonetheless, this new study suggests that dopamine cell loss could be associated with RBD onset, which also supports imaging studies showing dopamine cell loss in patients with RBD [64]. Dysfunction of normal inhibitory neurotransmission has also been linked to RBD. Transgenic mice with reduced GABA and glycine receptor function develop the major symptoms of RBD, including behavioral, motor, and EEG phenotypes (Figure 4). It is not surprising that impaired inhibitory neurotransmission is associated with RBD behaviors, because REM sleep atonia is caused by GABA- and/or glycine-mediated inhibition of skeletal motoneurons [15], and damage to glycine- and/or GABA-rich brainstem regions can trigger an RBD-like syndrome [93,102,103]. Recently, Brooks and Peever found that transgenic mice with deficient glycine and GABAA receptor function exhibited the cardinal features of RBD [11] (Figure 4). For example, these mice exhibited overt motor behaviors (e.g., chewing and grooming) during REM sleep, and they experienced repeated muscle jerks and twitches during nonREM sleep, which are common in patients with RBD [3]. Transgenic mice also had moderate sleep disruption and marked EEG slowing, which can both occur in RBD [55] (Figure 4). Importantly, RBD symptoms were alleviated by clonazepam and melatonin, which are the most common and effective treatment for RBD symptoms. These findings are important because they are the first to link a potential genetic mechanism to RBD. Therefore, this model could be a useful resource for investigating in vivo disease mechanisms and developing potential therapeutics for RBD. These findings also emphasize the need to determine whether impairments in CNS inhibitory transmission contribute to human RBD. Disease mechanisms in RBD Brainstem lesions due to neurodegeneration, tumors, or ischemic injury can trigger RBD motor symptoms in some patients. Neuroimaging studies show that damage within or near the mesencephalic and pontine tegmental regions is associated with RBD symptoms [12,103,107–110]. It is important to realize that these regions broadly include the SLD and caudal ventromedial medulla that underlie generation of REM sleep atonia (Figure 2). In fact, a recent functional imaging study showed that magnitude of neuronal loss in the subcoeruleus strongly correlates with REM sleep without atonia in patients with RBD and comorbid PD, but not in patients with PD but without RBD
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Figure 4. Impaired inhibitory transmission triggers cardinal features of rapid eye movement (REM) sleep behavior disorder (RBD) in mice. (A) Electromyographic (EMG) and electroencephalographic (EEG) traces showing that, compared with wild type (Wt) mice, transgenic mice (Tg) exhibit elaborate motor activity during REM sleep. (B) EMG and EEG traces from a Wt and a Tg mouse showing that Tg mice experience brief, repetitive muscle twitches and/or jerks during nonREM sleep. (C) Hypnograms showing that, unlike Wt mice, Tg mice have markedly fragmented sleep, experiencing more transitions into and out of nonREM and REM sleep. (D) Waking EEG spectral profiles for Wt and Tg mice showing that Tg animals have more power in the lower frequency ranges and less power in the higher frequency ranges (i.e., EEG slowing). (E) Graphs showing that high levels of muscle tone in RBD mice are reduced by clonazepam and melatonin. Modified from [11].
[13]. This link suggests that loss of subcoeruleus neurons is the primary cause of REM motor behaviors in RBD. Postmortem studies of brain tissue from patients with RBD are also valuable resources for identifying potential disease mechanisms [1,6]. The most consistent and striking finding is the presence of Lewy bodies in the brainstem
structures associated with control of REM sleep atonia [33,110,111]. Lewy bodies, neuronal loss, depigmentation, and/or gliosis are located in (or near) the subcoeruleus, gigantocellular reticular nucleus, and pedunculopontine nucleus (Figure 3) [1,102,112–117]. These findings not only support neuroimaging data showing that neuronal cell loss 7
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Review in these areas is associated with RBD pathogenesis [12,13], but also substantiate basic neuroscience data showing that lesions positioned in these brainstem regions prevent REM sleep atonia [87,93–95]. Patients with RBD also exhibit changes in normal cholinergic system activity. Neuroimaging studies suggest that patients with both RBD and PD have significant degeneration of brain cholinergic systems, whereas, patients with PD but not RBD have normal cholinergic activity levels [118]. Given that a cholinergic mechanism functions to promote REM sleep atonia [119,120], it is possible that degeneration of brainstem cholinergic systems could underlie motor symptoms in patients with RBD and PD. Patients with RBD also experience pathological changes in basal ganglia anatomy. Neuroimaging studies show reduced striatal dopamine transporter expression and reduced striatal dopaminergic terminal densities in patients with RBD [64,116,117]. Pathological changes within the substantia nigra have also been reported in RBD [121]. A recent study found reduced striatal dopamine transporter expression in patients with RBD but without co-morbid PD symptoms, suggesting that dopamine dysfunction is associated with RBD [64]. The potential link between dopamine system dysfunction and RBD is also supported by findings showing a significant correlation between levels of REM sleep atonia and striatal dopaminergic terminal density in patients with RBD and MSA [122]. However, it is debatable whether the dopamine system has a direct role in RBD because only 30–60% of patients with PD exhibit RBD [4]. Instead, it is more likely that dopamine cell loss in RBD is associated with the pathological changes that underlie PD. It is well documented that neuronal damage begins in the lower brainstem before it progresses rostrally to affect the nigral circuits whose degeneration results in parkinsonian features [6]. It is important to realize that early degenerative processes in PD encompass the medullary and pontine circuits that control REM sleep atonia, which likely explains why RBD symptoms begin years before PD symptoms occur. However, because patients with RBD often exhibit mild cognitive impairment [44], this suggests that disease processes also impact rostral brain structures during early stages of RBD. Future directions Animal research has provided valuable insight into potential disease mechanisms in RBD [14,87]. Basic neuroscience studies have determined that REM sleep atonia is triggered by a two-part brainstem circuit (Figure 2) that, when experimentally lesioned, produces RBD symptoms in animals. Degeneration of this circuitry is associated with REM motor behaviors in RBD, suggesting that breakdown of REM sleep circuits underlies the disorder. Although initial studies suggest that REM atonia is triggered by SLD cells [91], their neurotransmitter phenotype remains ill defined. Future basic science studies need to focus on not only better characterization of REM generating circuits, but also understanding why such circuits are vulnerable to degeneration in RBD. RBD is more tightly linked to synucleinopathies than it is to tauopathies and other neurodegenerative disorders 8
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[6,7,28]. This correlation suggests that synucleinopathies impact the brainstem systems that control REM sleep, whereas tauopathies do not. Therefore, determining differences in brainstem physiology and anatomy between synucleinopathies and nonsynucleinopathies should provide a useful framework for identifying potential neural substrates of RBD. Identifying pathological changes in postmortem brainstem tissue from patients with RBD and concomitant synucleinopathies (e.g., PD) will help to establish a functional link between RBD and neurodegenerative processes. In idiopathic RBD, motor symptoms during REM sleep worsen with time [123], suggesting that progressive neuronal degeneration contributes to RBD symptoms. The possibility to study longitudinally prodromal markers years before disease onset has major scientific and clinical implications. It could help determine the sequence of cell loss in RBD and pinpoint the systems responsible for RBD onset and progression. Finding a way to identify those patients with RBD at even higher short-term risk of developing neurodegeneration will be important for the development of neuroprotective interventions. Clinical trials of this nature offer enormous potential in understanding the mechanistic underpinnings of RBD and their related neurodegenerative disorders. Acknowledgments J.P. was supported by research funding from NSERC and CIHR. J.M. was supported by research funds from CIHR. The authors thank Dominique Petit and Zoltan Torontali for their technical assistance.
References 1 Iranzo, A. et al. (2013) Neurodegenerative disease status and postmortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol. 12, 443–453 2 Dauvilliers, Y. et al. (2013) Family history of idiopathic REM behavior disorder: a multicenter case-control study. Neurology 80, 2233–2235 3 Schenck, C.H. and Mahowald, M.W. (2002) REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 25, 120–138 4 De Cock, V.C. et al. (2007) Restoration of normal motor control in Parkinson’s disease during REM sleep. Brain 130, 450–456 5 Schenck, C.H. and Mahowald, M.W. (1996) REM sleep parasomnias. Neurol. Clin. 14, 697–720 6 Boeve, B.F. (2013) Idiopathic REM sleep behaviour disorder in the development of Parkinson’s disease. Lancet Neurol. 12, 469–482 7 Iranzo, A. et al. (2006) Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol. 5, 572–577 8 Boissard, R. et al. (2003) Localization of the GABAergic and nonGABAergic neurons projecting to the sublaterodorsal nucleus and potentially gating paradoxical sleep onset. Eur. J. Neurosci. 18, 1627– 1639 9 Boissard, R. et al. (2002) The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study. Eur. J. Neurosci. 16, 1959–1973 10 Luppi, P.H. et al. (2011) The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder. Sleep Med. Rev. 15, 153–163 11 Brooks, P.L. and Peever, J.H. (2011) Impaired GABA and glycine transmission triggers cardinal features of rapid eye movement sleep behavior disorder in mice. J. Neurosci. 31, 7111–7121 12 Scherfler, C. et al. (2011) White and gray matter abnormalities in idiopathic rapid eye movement sleep behavior disorder: a diffusiontensor imaging and voxel-based morphometry study. Ann. Neurol. 69, 400–407
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Review 13 Garcia-Lorenzo, D. et al. (2013) The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease. Brain 136, 2120–2129 14 Brooks, P.L. and Peever, J.H. (2008) Glycinergic and GABA(A)mediated inhibition of somatic motoneurons does not mediate rapid eye movement sleep motor atonia. J. Neurosci. 28, 3535–3545 15 Brooks, P.L. and Peever, J.H. (2012) Identification of the transmitter and receptor mechanisms responsible for REM sleep paralysis. J. Neurosci. 32, 9785–9795 16 Schenck, C.H. et al. (2009) Potentially lethal behaviors associated with rapid eye movement sleep behavior disorder: review of the literature and forensic implications. J. Forensic Sci. 54, 1475–1484 17 Oudiette, D. et al. (2009) Nonviolent elaborate behaviors may also occur in REM sleep behavior disorder. Neurology 72, 551–557 18 Fantini, M.L. et al. (2005) Aggressive dream content without daytime aggressiveness in REM sleep behavior disorder. Neurology 65, 1010– 1015 19 American Academy of Sleep Medicine (2005) International Classification Of Sleep Disorders 2, American Academy of Sleep Medicine 20 Frauscher, B. et al. (2012) Normative EMG values during REM sleep for the diagnosis of REM sleep behavior disorder. Sleep 35, 835–847 21 Fantini, M.L. et al. (2002) Periodic leg movements in REM sleep behavior disorder and related autonomic and EEG activation. Neurology 59, 1889–1894 22 Ohayon, M.M. et al. (1997) Violent behavior during sleep. J. Clin. Psychiatry 58, 369–376 quiz 377 23 Kang, S.H. et al. (2013) REM sleep behavior disorder in the Korean elderly population: prevalence and clinical characteristics. Sleep 36, 1147–1152 24 Boot, B.P. et al. (2012) Probable rapid eye movement sleep behavior disorder increases risk for mild cognitive impairment and Parkinson disease: a population-based study. Ann. Neurol. 71, 49–56 25 Bjornara, K.A. et al. (2013) REM sleep behavior disorder in Parkinson’s disease: is there a gender difference? Parkinsonism Relat. Disord. 19, 120–122 26 Schenck, C.H. et al. (1996) HLA class II genes associated with REM sleep behavior disorder. Ann. Neurol. 39, 261–263 27 Postuma, R.B. et al. (2012) Environmental risk factors for REM sleep behavior disorder: a multicenter case-control study. Neurology 79, 428–434 28 Gagnon, J.F. et al. (2006) Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases. Lancet Neurol. 5, 424–432 29 Manni, R. et al. (2011) Secondary ‘‘incidental’’ REM sleep behavior disorder: do we ever think of it? Sleep Med. 12 (Suppl. 2), S50–S53 30 Gagnon, J.F. et al. (2002) REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease. Neurology 59, 585–589 31 Sixel-Doring, F. et al. (2011) Associated factors for REM sleep behavior disorder in Parkinson disease. Neurology 77, 1048–1054 32 Ferman, T.J. et al. (2011) Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies. Neurology 77, 875–882 33 Boeve, B.F. et al. (1998) REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease. Neurology 51, 363–370 34 Iranzo, A. et al. (2005) Characteristics of idiopathic REM sleep behavior disorder and that associated with MSA and PD. Neurology 65, 247–252 35 Gagnon, J.F. et al. (2006) Update on the pharmacology of REM sleep behavior disorder. Neurology 67, 742–747 36 Winkelman, J.W. and James, L. (2004) Serotonergic antidepressants are associated with REM sleep without atonia. Sleep 27, 317–321 37 Olson, E.J. et al. (2000) Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 123, 331–339 38 Bonakis, A. et al. (2009) REM sleep behaviour disorder (RBD) and its associations in young patients. Sleep Med. 10, 641–645 39 Dauvilliers, Y. et al. (2007) REM sleep characteristics in narcolepsy and REM sleep behavior disorder. Sleep 30, 844–849 40 Buskova, J. et al. (2010) Olfactory dysfunction in narcolepsy with and without cataplexy. Sleep Med. 11, 558–561 41 Bayard, S. et al. (2010) Olfactory dysfunction in narcolepsy with cataplexy. Sleep Med. 11, 876–881 42 Oudiette, D. et al. (2012) A motor signature of REM sleep behavior disorder. Mov. Disord. 27, 428–431
Trends in Neurosciences xxx xxxx, Vol. xxx, No. x
43 Schenck, C.H. et al. (1996) Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 46, 388– 393 44 Postuma, R.B. et al. (2009) Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology 72, 1296–1300 45 Wing, Y.K. et al. (2012) Prospective outcome of rapid eye movement sleep behaviour disorder: psychiatric disorders as a potential early marker of Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 83, 470–472 46 Schenck, C.H. et al. (2013) Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med. 14, 744–748 47 Claassen, D.O. et al. (2010) REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology 75, 494–499 48 Postuma, R.B. et al. (2006) Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder. Neurology 66, 845–851 49 Postuma, R.B. et al. (2012) How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. Brain 135, 1860–1870 50 Massicotte-Marquez, J. et al. (2008) Executive dysfunction and memory impairment in idiopathic REM sleep behavior disorder. Neurology 70, 1250–1257 51 Fantini, M.L. et al. (2005) Idiopathic REM sleep behavior disorder: toward a better nosologic definition. Neurology 64, 780–786 52 Ferini-Strambi, L. et al. (1996) Cardiac autonomic activity during wakefulness and sleep in REM sleep behavior disorder. Sleep 19, 367– 369 53 Lanfranchi, P.A. et al. (2007) Cardiac autonomic regulation during sleep in idiopathic REM sleep behavior disorder. Sleep 30, 1019–1025 54 Postuma, R.B. et al. (2013) Prodromal autonomic symptoms and signs in Parkinson’s disease and dementia with Lewy bodies. Mov. Disord. 28, 597–604 55 Fantini, M.L. et al. (2003) Slowing of electroencephalogram in rapid eye movement sleep behavior disorder. Ann. Neurol. 53, 774–780 56 Iranzo, A. et al. (2010) Electroencephalographic slowing heralds mild cognitive impairment in idiopathic REM sleep behavior disorder. Sleep Med. 11, 534–539 57 Vendette, M. et al. (2011) Brain perfusion and markers of neurodegeneration in rapid eye movement sleep behavior disorder. Mov. Disord. 26, 1717–1724 58 Chaudhuri, K.R. (2001) Autonomic dysfunction in movement disorders. Curr. Opin. Neurol. 14, 505–511 59 Diederich, N.J. et al. (2002) Progressive worsening of spatial and chromatic processing deficits in Parkinson disease. Arch. Neurol. 59, 1249–1252 60 Katzenschlager, R. and Lees, A.J. (2004) Olfaction and Parkinson’s syndromes: its role in differential diagnosis. Curr. Opin. Neurol. 17, 417–423 61 Mosimann, U.P. et al. (2004) Visual perception in Parkinson disease dementia and dementia with Lewy bodies. Neurology 63, 2091–2096 62 Ponsen, M.M. et al. (2004) Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann. Neurol. 56, 173–181 63 Dang-Vu, T.T. et al. (2012) Hippocampal perfusion predicts impending neurodegeneration in REM sleep behavior disorder. Neurology 79, 2302–2306 64 Iranzo, A. et al. (2011) Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eyemovement sleep behaviour disorder: a prospective study. Lancet Neurol. 10, 797–805 65 Fantini, M.L. et al. (2003) The effects of pramipexole in REM sleep behavior disorder. Neurology 61, 1418–1420 66 Schmidt, M.H. et al. (2006) Use of pramipexole in REM sleep behavior disorder: results from a case series. Sleep Med. 7, 418–423 67 Kumru, H. et al. (2008) Lack of effects of pramipexole on REM sleep behavior disorder in Parkinson disease. Sleep 31, 1418–1421 68 Sasai, T. et al. (2012) Effectiveness of pramipexole, a dopamine agonist, on rapid eye movement sleep behavior disorder. Tohoku J. Exp. Med. 226, 177–181 9
TINS-1044; No. of Pages 10
Review 69 Aurora, R.N. et al. (2010) Best practice guide for the treatment of REM sleep behavior disorder (RBD). J. Clin. Sleep Med. 6, 85–95 70 Mahowald, M.W. and Schenck, C.H. (2005) REM sleep parasomnias. In Principles and Practices of Sleep Medicine (Kryger, M.H. et al., eds), pp. 897–916, Saunders 71 Ferri, R. et al. (2013) Effects of long-term use of clonazepam on nonrapid eye movement sleep patterns in rapid eye movement sleep behavior disorder. Sleep Med. 14, 399–406 72 Kunz, D. and Mahlberg, R. (2010) A two-part, double-blind, placebocontrolled trial of exogenous melatonin in REM sleep behaviour disorder. J. Sleep Res. 19, 591–596 73 Boeve, B.F. et al. (2003) Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med. 4, 281–284 74 McCarter, S.J. et al. (2013) Treatment outcomes in REM sleep behavior disorder. Sleep Med. 14, 237–242 75 Nakamura, Y. et al. (1978) Intracellular analysis of trigeminal motoneuron activity during sleep in the cat. Science 199, 204–207 76 Soja, P.J. et al. (1991) The postsynaptic inhibitory control of lumbar motoneurons during the atonia of active sleep: effect of strychnine on motoneuron properties. J. Neurosci. 11, 2804–2811 77 Kodama, T. et al. (2003) Changes in inhibitory amino acid release linked to pontine-induced atonia: an in vivo microdialysis study. J. Neurosci. 23, 1548–1554 78 McGinty, D.J. and Harper, R.M. (1976) Dorsal raphe neurons: depression of firing during sleep in cats. Brain Res. 101, 569–575 79 Lai, Y.Y. et al. (2001) Changes in monoamine release in the ventral horn and hypoglossal nucleus linked to pontine inhibition of muscle tone: an in vivo microdialysis study. J. Neurosci. 21, 7384–7391 80 Burgess, C. et al. (2008) An endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone across the sleep-wake cycle. J. Neurosci. 28, 4649–4660 81 Chan, E. et al. (2006) Endogenous excitatory drive modulating respiratory muscle activity across sleep-wake states. Am. J. Respir. Crit. Care Med. 174, 1264–1273 82 Fenik, V.B. et al. (2005) REM sleep-like atonia of hypoglossal (XII) motoneurons is caused by loss of noradrenergic and serotonergic inputs. Am. J. Respir. Crit. Care Med. 172, 1322–1330 83 Trulson, M.E. et al. (1981) Raphe unit activity during REM sleep in normal cats and in pontine lesioned cats displaying REM sleep without atonia. Brain Res. 226, 75–91 84 Soja, P.J. et al. (1995) Effects of excitatory amino acid antagonists on the phasic depolarizing events that occur in lumbar motoneurons during REM periods of active sleep. J. Neurosci. 15, 4068–4076 85 Siegel, J.M. et al. (1986) Behavioral states in the chronic medullary and midpontine cat. Electroencephalogr. Clin. Neurophysiol. 63, 274–288 86 Luppi, P.H. et al. (2013) Paradoxical (REM) sleep genesis by the brainstem is under hypothalamic control. Curr. Opin. Neurobiol. 23, 786–792 87 Lu, J. et al. (2006) A putative flip-flop switch for control of REM sleep. Nature 441, 589–594 88 Baghdoyan, H.A. et al. (1984) Site-specific enhancement and suppression of desynchronized sleep signs following cholinergic stimulation of three brainstem regions. Brain Res. 306, 39–52 89 Siegel, J.M. et al. (1991) Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla. Science 252, 1315–1318 90 Maloney, K.J. et al. (1999) Differential c-Fos expression in cholinergic, monoaminergic, and GABAergic cell groups of the pontomesencephalic tegmentum after paradoxical sleep deprivation and recovery. J. Neurosci. 19, 3057–3072 91 Clement, O. et al. (2011) Evidence that neurons of the sublaterodorsal tegmental nucleus triggering paradoxical (REM) sleep are glutamatergic. Sleep 34, 419–423 92 Lai, Y.Y. and Siegel, J.M. (1988) Medullary regions mediating atonia. J. Neurosci. 8, 4790–4796 93 Schenkel, E. and Siegel, J.M. (1989) REM-sleep without atonia after lesions of the medial medulla. Neurosci. Lett. 98, 159–165 94 Holmes, C.J. et al. (1994) Distribution of cholinergic, GABAergic and serotonergic neurons in the medial medullary reticular formation and their projections studied by cytotoxic lesions in the cat. Neuroscience 62, 1155–1178 95 Vetrivelan, R. et al. (2009) Medullary circuitry regulating rapid eye movement sleep and motor atonia. J. Neurosci. 29, 9361–9369 10
Trends in Neurosciences xxx xxxx, Vol. xxx, No. x
96 Lim, A.S. et al. (2007) Characterization of REM-sleep associated ponto-geniculo-occipital waves in the human pons. Sleep 30, 823–827 97 Karlsson, K.A. et al. (2005) The neural substrates of infant sleep in rats. PLoS Biol. 3, e143 98 Gassel, M.M. et al. (1966) Rubrospinal influences during desynchronized sleep. Nature 209, 1218–1220 99 Grace, K.P. et al. (2012) 5-HT1A receptor-responsive pedunculopontine tegmental neurons suppress REM sleep and respiratory motor activity. J. Neurosci. 32, 1622–1633 100 Evarts, E.V. (1964) Temporal patterns of discharge of pyramidal tract neurons during sleep and waking in the monkey. J. Neurophysiol. 27, 152–171 101 Brown, R.E. et al. (2012) Control of sleep and wakefulness. Physiol. Rev. 92, 1087–1187 102 Boeve, B.F. et al. (2007) Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 130, 2770–2788 103 Mathis, J. et al. (2007) Isolated mediotegmental lesion causing narcolepsy and rapid eye movement sleep behaviour disorder: a case evidencing a common pathway in narcolepsy and rapid eye movement sleep behaviour disorder. J. Neurol. Neurosurg. Psychiatry 78, 427–429 104 Karlsson, K.A. and Blumberg, M.S. (2005) Active medullary control of atonia in week-old rats. Neuroscience 130, 275–283 105 Jouvet, M. (1962) Recherches sur les structures nerveuses et les mecanismes responsables des differentes phases du sommeil physiologique. Arch. Ital. Biol. 100, 125–206 106 Verhave, P.S. et al. (2011) REM sleep behavior disorder in the marmoset MPTP model of early Parkinson disease. Sleep 34, 1119– 1125 107 Provini, F. et al. (2004) Status dissociatus after surgery for tegmental ponto-mesencephalic cavernoma: a state-dependent disorder of motor control during sleep. Mov. Disord. 19, 719–723 108 Tippmann-Peikert, M. et al. (2006) REM sleep behavior disorder initiated by acute brainstem multiple sclerosis. Neurology 66, 1277–1279 109 Plazzi, G. and Montagna, P. (2002) Remitting REM sleep behavior disorder as the initial sign of multiple sclerosis. Sleep Med. 3, 437–439 110 Schenck, C.H. et al. (1996) A case of REM sleep behavior disorder with autopsy-confirmed Alzheimer’s disease: postmortem brain stem histochemical analyses. Biol. Psychiatry 40, 422–425 111 Uchiyama, M. et al. (1995) Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology 45, 709–712 112 Benarroch, E.E. (2002) New findings on the neuropathology of multiple system atrophy. Auton. Neurosci. 96, 59–62 113 Turner, R.S. et al. (2000) The pathology of REM sleep behavior disorder with comorbid Lewy body dementia. Neurology 55, 1730–1732 114 Schenck, C.H. et al. (1997) Lewy body variant of Alzheimer’s disease (AD) identified by postmortem ubiquitin staining in a previously reported case of AD associated with REM sleep behavior disorder. Biol. Psychiatry 42, 527–528 115 Boeve, B. et al. (2003) Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 61, 40– 45 116 Albin, R.L. et al. (2000) Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurology 55, 1410–1412 117 Eisensehr, I. et al. (2000) Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder - Comparison with Parkinson’s disease and controls. Brain 123, 1155–1160 118 Kotagal, V. et al. (2012) Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease. Ann. Neurol. 71, 560–568 119 Grace, K.P. et al. (2012) Identification of the mechanism mediating genioglossus muscle suppression in REM sleep. Am. J. Respir. Crit. Care Med. 187, 311–319 120 Torontali, Z. et al. (2014) Cholinergic involvement in control of REM sleep paralysis. J. Physiol. (in press) 121 Miyamoto, M. et al. (2012) Preclinical substantia nigra dysfunction in rapid eye movement sleep behaviour disorder. Sleep Med. 13, 102–106 122 Gilman, S. et al. (2003) REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA. Neurology 61, 29–34 123 Iranzo, A. et al. (2009) Excessive muscle activity increases over time in idiopathic REM sleep behavior disorder. Sleep 32, 1149–1153
