Neurophysiological basis of rapid eye movement sleep behavior disorder: informing future drug development

Abstract

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by a history of recurrent nocturnal dream enactment behavior and loss of skeletal muscle atonia and increased phasic muscle activity during REM sleep: REM sleep without atonia. RBD and associated comorbidities have recently been identified as one of the most specific and potentially sensitive risk factors for later development of any of the alpha-synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and other atypical parkinsonian syndromes. Several other sleep-related abnormalities have recently been identified in patients with RBD/Parkinson's disease who experience abnormalities in sleep electroencephalographic frequencies, sleep-wake transitions, wake and sleep stability, occurrence and morphology of sleep spindles, and electrooculography measures. These findings suggest a gradual involvement of the brainstem and other structures, which is in line with the gradual involvement known in these disorders. We propose that these findings may help identify biomarkers of individuals at high risk of subsequent conversion to parkinsonism.

Keywords: brain stem; hypocretin; hypothalamus; motor control.

Figure 1

Examples of potential PD biomarkers expressed in polysomnographic signals and their neuroanatomical correlates. Notes: Sleep is mainly controlled by two mutually dependent neuronal control loops illustrated by blue (wake–sleep) and red (REM–NREM). Disruption in any of these may be expressed electrophysiologically in the EEG, EOG, or EMG or in the hypnogram. During REM sleep, a descending branch of neurons from the SLD projects into medullary premotor neurons generating atonia, which electrophysiologically can be measured in the EMG and EOG signals. An ascending branch of neurons from the SLD projects into rostral brain areas responsible for the cortical activation during REM sleep, expressed electrophysiologically in the EEG as, eg, sawtooth waves. During REM sleep, characteristic REMs controlled by the saccadic control mechanisms are expressed in the EOG signals. During NREM sleep, the sleep promoting pathway inhibits the ascending arousal pathways introducing slowing of the EEG as well as sleep-specific events expressed electrophysiologically in the EEG as, eg, delta waves or sleep spindles. In all these examples, the involved neurons can be vulnerable to early neurodegeneration as seen in PD and can thus serve as electrophysiological PD biomarkers. Abbreviations: PD, Parkinson’s disease; REM, rapid eye movement; NREM, nonrapid eye movement; EEG; electroencephalogram; EOG, electrooculography; EMG, electromyography; SLD, sublaterodorsal region; VLPO/MnPO, ventrolateral/median preoptic nucleus; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; LC, locus coeruleus; PC, precoeruleus area; DR, dorsal raphe nucleus; vPAG, ventral periaqueductal gray; TMN, tuberomammillary nucleus; vlPAG, ventrolateral periaqueductal gray matter; LPT, lateral pontine tegmentum; BF, basal forebrain.