This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.

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Control of Sleep and Wakefulness

Rapid eye movement (REM) sleep consists of a dreaming state in which there is activation of the cortical and hippocampal electroencephalogram (EEG), rapid eye movements, and loss of muscle tone. Although REM sleep was discovered more than 50 years ago, the neuronal circuits responsible for switching between REM and non-REM (NREM) sleep remain poorly understood. Here we propose a brainstem flip–flop switch, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. Each side contains GABA (γ-aminobutyric acid)-ergic neurons that heavily innervate the other. The REM-on area also contains two populations of glutamatergic neurons. One set projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates atonia during REM sleep. The mutually inhibitory interactions of the REM-on and REM-off areas may form a flip–flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions—for example, in narcolepsy. Rapid eye movement (REM) sleep is a dreaming state in which the brain is highly active. The mechanism responsible for switching between REM and non-REM sleep (also called slow-wave sleep, when cortical activity is slow) is poorly understood. Now, based on detailed anatomy and lesion experiments, Lu et al. have identified brainstem regions that control the transition from REM to non-REM sleep. The REM-off and REM-on areas are mutually inhibitory. This appears to produce a flip-flop switch relationship that could explain many of the properties of the abrupt switching into and out of REM states seen in sleep disorders such as narcolepsy.

A putative flip–flop switch for control of REM sleep

REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease ('secondary RBD') is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with 'idiopathic' RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in patients with idiopathic RBD, to further elucidate the pathophysiology and also characterize the clinical and pathophysiological relevance of RBD in neurodegenerative disease. Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials.

/pdf/pathophysiology-of-rem-sleep-behaviour-disorder-and-4m6fd57m2a.pdf

Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease

/pdf/rem-sleep-behavior-disorder-clinical-developmental-and-28t5l9f2sr.pdf

REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP.

Summary of Recommendations:
Modifying the sleep environment is recommended for the treatment of patients with RBD who have sleep-related injury. Level A

Clonazepam is suggested for the treatment of RBD but should be used with caution in patients with dementia, gait disorders, or concomitant OSA. Its use should be monitored carefully over time as RBD appears to be a precursor to neurodegenerative disorders with dementia in some patients. Level B

Clonazepam is suggested to decrease the occurrence of sleep-related injury caused by RBD in patients for whom pharmacologic therapy is deemed necessary. It should be used in caution in patients with dementia, gait disorders, or concomitant OSA, and its use should be monitored carefully over time. Level B

Melatonin is suggested for the treatment of RBD with the advantage that there are few side effects. Level B

Pramipexole may be considered to treat RBD, but efficacy studies have shown contradictory results. There is little evidence to support the use of paroxetine or L-DOPA to treat RBD, and some studies have suggested that these drugs may actually induce or exacerbate RBD. There are limited data regarding the efficacy of acetylcholinesterase inhibitors, but they may be considered to treat RBD in patients with a concomitant synucleinopathy. Level C

The following medications may be considered for treatment of RBD, but evidence is very limited with only a few subjects having been studied for each medication: zopiclone, benzodiazepines other than clonazepam, Yi-Gan San, desipramine, clozapine, carbamazepine, and sodium oxybate. Level C

Best Practice Guide for the Treatment of REM Sleep Behavior Disorder (RBD)

REM sleep behavior disorder (RBD) is characterized by lack of atonia of major muscle groups during REM sleep associated with excessive movement related to dreaming.1 Various neurodegenerative diseases involving brainstem structures have been reported to be associated with RBD.2 We report a patient with RBD with the sole lesion in the pontine reticular formation that could cause the abnormality of REM-mediated muscle atonia.

A 75-year-old woman was admitted to our hospital complaining of frequent episodes of transient dizziness and abnormal nocturnal behavior. This behavior started about 10 years before, when she also had a TIA manifesting as transient weakness in the right upper and lower extremities. She had a 9-year history of diabetes mellitus and hypertension, both of which were well controlled on diet and exercise therapy. Her nocturnal behavior was characterized by waving her arms, beating herself at the wall, and kicking the bedclothes. During these episodes, she often shouted because she became angry with employees of her company in her …

A discrete pontine ischemic lesion could cause REM sleep behavior disorder.

Since 1994, we have treated 62 cases with hyperacute cerebral embolism with local intraarterial thrombolysis (LIT), but not all cases showed recanalization. We tried to classify these cases by angiographic results. Angiographically they could be classified into four types; tapering type, fading type, stump type, and edge type. The tapering and fading type had a significantly higher tendency to recanalize than the stump and edge type. We think these classifications indicate the dissolubility of the cerebral emboli; the former two types dissoluble, the latter two types indissoluble. The tapering and fading type are the good indicators for LIT, but the stump and edge type may not be.

Angiographic classification of cerebral embolism. Relation with the response to local intra-arterial thrombolysis.

This case involved a 72-year-old woman. From the day after mitral annuloplasty, a fever over 37°C and ballismus-like involuntary movements of the right upper and lower limbs appeared. A few month later, involuntary movements spread throughout the body, and she developed impairment of consciousness and difficulty speaking and eating. Levels of protein in cerebrospinal fluid were high. Positive results were seen for serum mumps immunoglobulin G and M antibody. Because steroid pulse therapy proved effective, we suspected autoimmune encephalitis associated with mumps virus infection.

Y. Otsuka

Papers

A discrete pontine ischemic lesion could cause REM sleep behavior disorder.

Angiographic classification of cerebral embolism. Relation with the response to local intra-arterial thrombolysis.

A case of autoimmune encephalitis with involuntary movements as the first symptom and suspected association with mumps virus infection.