REM sleep is also defined as paradoxical sleep because of brain’s intense activity that is similar to the typical one of wakefulness: overall brain activity is maximal, but motor output is minimal. There aren’t different phases such as during NREM sleep. Muscle tone and motor reflexes are reduced during NREM sleep, but virtually eliminated during REM sleep.
During REM sleep the CNS is intensely active, but the skeletal motor system is paradoxically forced into a state of muscle paralysis. The mechanisms that trigger REM sleep paralysis are a matter of intense debate.
Skeletal muscle paralysis is a defining feature of normal REM sleep such as the rapid and irregular eye movements. The REM phase is also linked to dreams : people that are woken up during REM sleep generally refer about what they were dreaming. The probable function of atonia is to prevent the dreaming brain from triggering unwanted and potentially dangerous sleep movements.
Determining the mechanisms triggering loss of motoneuron function during REM sleep is important because breakdown in REM sleep motor control underlies sleep disorders such as REM sleep behavior disorder (RBD) and cataplexy/narcolepsy.
REM sleep behavior disorder (RBD) is a parasomnia characterized by recurrent dream enactment
with excessive motor activity. In some patients, RBD precedes the development of neurodegenerative syndromes such as synucleinopathies, Parkinson disease (PD), multiple system atrophy (MSA), and dementia.
Mechanisms responsible for REM Sleep Paralysis
The skeletal motor system is able to disconnect itself from the REM- active brain by reducing somatic motoneuron activity and tone.
There was considerable controversy concerning neuronal mechanisms generating muscle atonia in REM sleep. The prevalent hypothesis was that glycinergic inhibition of somatic motoneurons was responsible of loss of postural muscle tone in REM sleep. It stemmed from observation that trigeminal and lumbar motoneurons are hyperpolarized by large amplitude IPSPs, that are reduced but not eliminated by antagonism of gylicinergic receptors.
However, studies of respiratory motor control in sleep have shown that neither glycinergic nor GABA A inhibition mediate the typical suppression of inspiratory muscle activity during REM sleep. Although inspiratory muscle suppression is not caused by this kind oh inhibition, it wasn’t clear whether these mechanisms were effectively responsible for triggering REM atonia in postural muscles.
Studies chose to examine the trigeminal-masseteric motor system because masseter muscle tone is potently suppressed during REM sleep and abnormal masseter function contributes to the pathogenesis of several sleep disorders including RBD (REM sleep behaviour disorder), obstructive apnea, and narcolepsy.
Pharmacological blockade of glycine receptors on trigeminal motoneurons does not prevent REM atonia.
It has been demonstrated that the tone of muscle during REM sleep is not mediated by glycinergic inhibition, indeed masseter atonia persists despite continued glycine receptor antagonism, obtained by perfusion of strychnine (glycine receptor antagonist). These results indicate that:
* a tonic glycine drive inhibits motoneurons during waking and NREM sleep
* a phasic glycinergic drive acts to suppress muscle twitches during REM sleep
* glycine inhibition of motoneurons is not sufficient to trigger REM atonia.
Pharmacological blockade of GABA A receptors on trigeminal motoneurons does not prevent REM atonia.
GABA is the brain's most common inhibitory neurotransmitter and since motoneurons are influenced by GABAergic process in REM sleep, it has been possible to assume that REM sleep motor atonia may be mediated by GABAergic inhibition: therefore it has been used bicuculline to antagonize GABA A receptors. However its perfusion had no effect on basal level of muscle tone during tonic REM sleep.
Pharmacological blockade of both glycine and GABA A receptors on trigeminal motoneurons does not prevent REM atonia.
Neither GABA A nor glycine-mediated inhibition of motoneurons are sufficient for triggering atonia. However, because motoneurons are concurrently inhibited by GABA and glycine during REM sleep and both transmitters are coreleased onto motoneutons, it has been hypothesized that both may be required for producing REM atonia. Through the simultaneous antagonization of glycine and GABA A receptors in the trigeminal motor pool, it is possible to obtain powerful stimulatory effects on masseter tone during both waking and NREM sleep. However this effect was immediately abolished at the transition from NREM sleep into REM sleep and then regained during post-REM waking.
REM atonia persists even when glycine and GABA A receptors are antagonized and trigeminal motoneurons are directly activated by AMPA.
Because the preceding experiments show that REM atonia could not be reversed by blockade of glycine and GABA A receptors, it was thought that atonia may be mediated by a disfacilitation of excitatory inputs onto motoneurons with a potent dose of AMPA.
The perfusion of a potent dose of AMPA, while both glycine and GABA A receptors were antagonized, increased muscle tone during both waking and NREM sleep. However , this excitatory effect was immediately abolished at the transition from NREM sleep into REM sleep, with REM atonia persisting despite simultaneous antagonism of both glycine and GABA A receptors and activation of AMPA receptors.
The most fundamental observation is that REM sleep atonia could not be reversed by either glycine or GABA A receptors antagonism. This finding contradicts the prevailing hypothesis that REM atonia is mediated by glycinergic inhibition of motoneurons. Although the strychnine unmasked a tonic inhibitory drive and increased basal masseter tone during waking and NREM sleep, it had no effect on REM atonia. Antagonism of either GABA A receptors alone or both glycine and GABA A receptors had no effect on REM sleep muscle atonia.
Deficient GABA A and glycine receptor function does not prevent REM sleep atonia
Studies on transgenic mice whose glycine and GABAA receptors had been impaired, were important for two different reasons: the first was to further define the role for GABA and glycine transmission in producing REM atonia, and the second one was to determine if impaired inhibition could trigger a motor phenotype that mimics human RBD. Transgenic mice were generated by expressing a mutant glycine receptor ?1 subunit in the mouse genome; mutant receptors were expressed throughout the central nervous system. In vitro cell recordings show that transgenic spinal neurons not only experience a 70% reduction in glycine receptor-mediated
inhibition, but they also exhibit a 91% reduction in GABAA receptor-mediated inhibition. The exact cause of reduced GABAA-mediated inhibition is unknown, but nonetheless transgenic
mice experience a potent reduction in both glycine and GABA A receptor-mediated inhibition. These mice therefore serve as a tool for assessing how deficits in inhibitory transmission
affect REM atonia. Despite almost complete loss of normal GABAA and glycine mediated inhibition, electrophysiological and behavioral data show that REM atonia is preserved
in masseter, neck and hindlimb muscles in transgenic mice. However, these transgenic mice have a marked exaggeration of muscle twitches during REM sleep episode despite maintenance of REM atonia. These results further indicate that GABA A and glycine neurotransmission play a negligible role mediating the loss of postural muscle tone in REM sleep.
These findings indicate that REM paralysis is triggered by a powerful, yet unidentified,
Recent studies have demonstrated that the inactivation of both metabotropic GABA B and ionotropic GABA A / glycine receptor prevented and indeed reversed REM paralysis. However neither metabotropic nor ionotropic pathways alone are sufficient for inducing REM inhibition. REM paralysis is only reversed when motoneurons are cut off form both metabotropic and ionotropic receptor- mediated inhibition. These results reshape the understanding of the transmitter and receptor mechanisms underlying REM sleep paralysis.
The activation of GABA B receptors on motoneurons reduced waking masseter muscle tone, indicating that receptor activation influences motoneuron behaviour. Nevertheless GABA B receptor agonism did not trigger complete muscle paralysis since waking masseter tone remained twofold above normal REM sleep levels. This finding suggests that GABA B receptor activation alone is incapable of inducing REM sleep muscle paralysis.
Blockade of GABA B, GABA A and glycine receptors prevents REM motor paralysis.
To identify these mechanisms, metabotropic GABA B and ionotropic GABA A/glycine receptors have been antagonized.
When all three receptors were antagonized masseter muscle tone increased to levels observed during normal NREM sleep. This effect is in contrast to blockade of only GABA A and glycine receptors, which had no influence on REM atonia. These findings suggest that REM paralysis is triggered when motoneurons are inhibited by concomitant activation of both metabotropic GABA B and ionotropic GABA A/ glycine receptors. Also the reduced motoneuron excitation contributes to REM paralysis.
These findings refute the long-standing hypothesis that one-transmitter, one-receptor phenomenon is responsible of REM paralysis. The inhibitory drive of REM sleep is far more pervasive than the relatively weak drive present during NREM sleep, which is easily blocked by inactivating either GABA A or glycine receptors. By comparison, REM motor inhibition is only rendered ineffective when motoneurons are completely deprived of both metabotropic GABA B and GABA A/ glycine receptor- mediated inhibition. Synergy between receptors function is a documented phenomenon in neuroscience. But dynamic interaction between GABA B, GABA A and glycine receptors is also evident: coactivation of GABA A and GABA B receptors produces more hyperpolarization than predicted by summation alone, moreover the cross talk between them and glycine receptors affects inhibition by second-messenger and receptor phosphorilation mechanisms.
Additional synaptic mechanisms could also influence motoneuron physiology and muscle tone during REM sleep: increased glycinergic inhibition is associated with decreased monoamniergic excitation of motoneurons. Reduced motoneurons excitation acts to reinforce muscle paralysis during REM sleep, therefore this paralysis results from a balance between motoneuron inhibition and reduced excitation.
Dysfunction of the REM-related inhibitory drive may explain the nature of REM sleep disorders such as RBD, sleep paralysis and narcolepsy. RBD results from loss of typical REM atonia , which allows pathological motor activation and dream enchantment which often lead to serious injuries. Sleep paralysis and cataplexy result when REM atonia intrudes into wakefulness thus preventing normal behaviour and movement. Determining the mechanistic nature of REM sleep paralysis will improve understanding and treatment of such disorders.
REM Sleep Behaviour Disorder
REM Sleep Behaviour Disorder is characterised by a loss of the normal muscle atonia that accompanies REM sleep. RBD occurs in approximately 0.5% of the general population, with a higher prevalence in older men. Affected patients have excessive motor activity such as punching , kicking or crying out in association with dream content: individuals appear to act out their dreams. The violent nature of some dream-enactment behaviours may cause severe injury to individuals with RBD or their bed partners.
It may be related to a degeneration of sleep regulating nuclei in the brain stem, especially in the pontine tegumentum. Several markers of neurodegeneration have been identified in RBD, including cognitive impairments such as deficits in attention, executive functions, learning capacities, and visuospatial abilities.
There are different forms of RBD. The acute form is triggered by certain psychotropic drugs (pharmacology-induced RBD), such as antidepressants. RBD is also strongly associated with certain neurological disorders, including narcolepsy, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, and Guillain–Barre syndrome. Symptomatic RBD can also be induced by focal lesions (vascular or inflammatory), tumors, or neurodegenerative processes in brainstem regions responsible for normal REM sleep muscle atonia. In fact, RBD is very frequent in synucleinopathies, a class of neurodegenerative diseases characterized by abnormal deposition of a-synuclein proteins. For instance, RBD affects about 33–46% of patients with Parkinson’s disease, 75% of patients with dementia with Lewy bodies (DLB), and almost 100% of patients with multiple system atrophy. Synucleinopathies share a common brainstem neurodegeneration with RBD, which may explain their strong association. On the other hand, RBD is rare in tau-related diseases such as Alzheimer’s disease (AD). RBD is therefore a useful feature to consider for differential diagnosis between DLB and AD. In fact, inclusion of RBD as a core clinical feature improves the DLB diagnosis accuracy . Finally, RBD can appear alone (“idiopathic” RBD or iRBD) without any associated condition. However, iRBD may be a risk factor for synucleinopathies.
Deficient GABA A and glycine receptor function triggers an RBD phenotype in transgenic mice.
Although the exact cause of RBD is unknown, abnormal glycine and GABA neurotransmission is
implicated in the disorder. First, strokes and lesions that affect brainstem regions containing glycine and GABA neurons triggers motor activation during REM sleep. Second, patients with impaired glycine and GABA transmission often experience heightened motor activity during sleep. Third, drugs that strengthen inhibitory function are the most common and effective treatment for RBD motor symptoms. Transgenic mice with deficient glycine and GABA transmission not only have REM motor activation, they also have the full complement of RBD symptoms that define the human disorder. All transgenic mice exhibit complex motor behaviours during REM : sleep-running, jerking and chewing are common behaviours.
Even though transgenic mice had increased phasic motor activity, they had normal levels of basal muscle tone. Excessive muscle twitch activity during REM sleep is reminiscent of human RBD and, therefore, recapitulates the primary human disease symptom.
Transgenic mice also displayed other disease features that typify human RBD. For example, they also suffer from pronounced sleep fragmentation. They awoke 135% and 34% more from NREM and REM sleep episodes than wild-type mice.
Transgenic mice also exhibited slowing in certain EEG frequencies, which is also a common feature inhuman RBD. Although gross EEG examination revealed no difference between wild-type and transgenic mice in waking or sleep, spectral analysis revealed greater EEG power in the theta range in transgenic mice. This cortical slowing is prominent during both waking and NREM sleep but not REM sleep. These findings mimic the EEG phenotype observed in human RBD patients. Importantly, the RBD motor phenotype is rescued by drugs (clonazepam and melatonin) that are routinely used to treat human disease symptoms. Clonazepam reduced overall EMG tone by 26% during REM sleep; it also reduced NREM muscle twitches by 51%. Moreover melatonin treatment reduced muscle twitches in REM sleep by 43% and improved sleep by alleviating sleep fragmentation. Together these data show that impaired inhibitory transmission triggers the hallmark features of RBD in transgenic mice. These findings not only identify a potential genetic mechanism for RBD, they also indicate that transgenic mice could serve as a resource for determining RBD pathogenesis.
This mouse model recapitulates all primary RBD features stemming from a defined genetic mutation. Transgenic mice are a useful model for determining how glycine and GABA transmission contribute to RBD development. These results also emphasize the need to determine if impaired glycine and GABA transmission also contribute to motor and sleep symptoms in human RBD.
Cognitive Decline in RBD.
Increasing evidence shows that iRBD patients perform poorly on neuropsychological tests.
However functional, results vary across studies depending on which cognitive domain is impaired . Population heterogeneity, small sample size, and the use of different cognitive tasks with variable sensitivity to detect deficits and variable specificity to a cognitive domain may explain these discrepancies. In general, attention, executive functions, episodic verbal memory (mainly free recall capacities), and non-verbal learning are the most affected domains in iRBD. Additionally, some studies reported in iRBD anomalies in visuospatial/visuoperceptive abilities, but this remains controversial. In fact, the presence of visuospatial (or non-verbal learning) impairment appears to be related to the extent of cognitive decline in iRBD patients, as reported in RBD-associated neurodegenerative diseases such as PD or DLB. On the other hand, language and praxis appear to be well preserved in iRBD, although these functions have received little research attention.
MCI in “idiopathic” RBD
Mild cognitive impairment is known to be an intermediate state between normal cognitive functioning and dementia. MCI can be diagnosed according to the following criteria: (1) subjective cognitive complaint by the patient or a relative, (2) cognitive decline on neuropsychological testing compared to age- and education-equivalent individuals, and (3) preserved daily life activities. MCI is a risk factor for dementia such as AD, DLB, or vascular dementia. However, the progression of MCI is also highly variable. Some MCI patients remain with mild cognitive deficits for many years whereas a substantial proportion return to normal cognitive functioning . Moreover, several factors may disrupt cognition in elderly individuals, so clinicians and researchers should be careful not to directly link MCI to the future development of a neurodegenerative disease or to consider MCI as part of a neurodegenerative disease.
Mild cognitive impairment is a frequent feature of iRBD. In iRBD patients referred to a sleep disorders center, MCI frequency was estimated at up to 50% compared to 8% in healthy subjects. No study to date has systematically followed a large cohort of iRBD patients with MCI to determine the risk of developing dementia. However, following seven iRBD patients for many years, it was noticed that all patients met MCI criteria and subsequently developed Lewy body disease, which was confirmed by autopsy. This suggests that iRBD patients with MCI are at higher risk for developing DLB.
Cognitive decline in PD associated with RBD
As mentioned , RBD is also a frequent feature of PD. RBD in PD patients has been associated with cognitive impairment, waking EEG slowing, a predominance of akinetic-rigid signs, symmetric disease, visual hallucinations, and autonomic dysfunction. It has been found a higher risk of having MCI in PD with concomitant RBD: MCI was present in 73% of PD patients with RBD compared to 11% of PD patients without RBD and 8% of healthy controls. Moreover, recently a prospective follow-up study has been conducted in a cohort of PD patients to assess whether the presence of polysomnographic-confirmed RBD at baseline predicted the future development of dementia according to neurological and neuropsychological assessments. The sample comprised 42 PD patients without dementia, including 27 with RBD and 15 without RBD. Over a mean 4-year follow-up, 48% of PD patients with RBD developed dementia, whereas none of PD patients without RBD converted to dementia. Although these results remain to be confirmed in a larger cohort of PD patients, they suggest that the presence of RBD in PD could indicate a more devastating and wide-spread neurodegenerative disease compared to PD patients without RBD symptoms.
The interval between RBD and the subsequent neurological syndrome ranged up to 50 years, with the median interval 25 years. Some studies have illustrated that pathogenic process of neurological disease may start decades before the first symptoms of PD. The long duration of this preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt neurodegenerative process.
The relationship of RBD and neurodegenerative disorders is documented by a research: according to it 40% of patients with isolated RBD later went on to develop Parkinson’s disease after a mean of 12,7 years. There are anecdotes of RBD symptomatology decades before presentation to a neurologist. Some of the most compelling histories involve RBD symptoms first noticed during a wedding honeymoon. These processes may sometimes have extremely long durations, with the neurodegenerative process beginning much earlier in life.
The main object of the study was to explore the extremely long duration of neurodegenerative process following patients with a 15 years of RBD history before the neurodegenerative disease.
The story of RBD included dream characterized by patients defending themselves from an attacker or running away from an attacking person or animal. They remember frightening dreams but could not recall the content. All bed partners confirmed motor behaviour during sleep. They included shouting, leaving the bed, flailing arm movements. In some cases this behaviour was noticed by partner early in marriage. Patients followed during this study presented clear dementia, had parkinsonism, orthostatic symptoms and some of them experienced hallucinations. At final review 10 of 28 patients had died. The median time to death from RBD onset was 37 years and from onset of cognitive changes was 7 years. 2 of them underwent autopsy that revealed brainstem and limbic areas as the predominant regions affected.
On average RBD precedes PD by around a decade but occasional cases had RBD documented more 15 years up to 50 before the neurodegenerative syndrome clinically manifested. These processes have very long durations of activity, often with long latencies when pathogenic process is active, but unapparent or marginally manifested.
Not all patients who initially present with isolated idiopathic RBD go to develop PD o DLB. However, the documenting very long latencies raises a question whether all patients would later develop such neurodegenerative syndromes if they lived long enough. RBD is likely overlooked since clinicians often do not ask about dream enactment behaviour and patients/family would not intuitively expect this to be relevant to later-developing of neurologic syndromes.
PD, DLB, MS may have extremely long courses with preclinical periods extending back decades in at least some cases. The pathogenic process may span most of the lifetime. This is relevant to epidemiologic studies investigating exposures. It is also highly relevant to the development of therapies that might slow the progression which could be implemented well before cognitive and motor features are manifest.
Obtaining an accurate picture of the risk of developing neurodegenerative disorder is essential for accurate counselling of patients and for planning of any potential neuroprotective trials.
This raised awareness of RBD, supported by the idea of developing any possible neuroprotective agents in future able to stop the progression. Identification of idiopathic RBD could help for initiating this treatment at the earliest stages of neurodegenerative disease.
Symptoms to diagnosis latency seems to be changing in time, which no doubt reflects increased awareness recognition of the disorders. Finally difference in analytic method between studies can result in important differences in estimation of disease risk. The last method of analysis was a life table analysis , while previous case series estimating risk of disease in RBD described the proportion developing disease, with mean follow up duration.
It was possible to estimate disease risk at 10- 12-year time points.
For treatment of RBD symptoms, clonazepam and melatonin are the two most commonly used pharmacological agents. Changing the sleep environment is also recommended to prevent injuries to the patient and the bed partner. Although the pathophysiology of RBD in humans is still debated, anomalies in the pontomedullary brainstem neural networks responsible for the suppression of muscle tone during REM sleep are strongly suspected.