The REM sleep circuit and how its impairment leads to REM sleep behavior disorder

Abstract

REM sleep is characterized by rapid eye movements, desynchronized electroencephalographic activity, dreams and muscle paralysis that preclude the individual from acting out the action of dreams. REM sleep is generated and modulated by a complex and still poorly understood, neuronal network that involves multiple nuclei and neurotransmission systems. The key structures that generate REM sleep muscle paralysis are the subcoeruleus nucleus in the mesopontine tegmentum and the reticular formation of the ventral medial medulla. Using glutamatergic, GABAergic and glycinergic inputs, direct and indirect projections from these two areas inhibit the motoneurons of the spinal cord resulting in skeletal paralysis in REM sleep. Experimental studies in cats and rodents where the subcoeruleus nucleus and ventral medial medulla were impaired by electrolytic, pharmacological and genetic manipulations have repeatedly produced increased electromyography activity during REM sleep associated with abnormal motor behaviors (e.g., prominent twitching, attack-like behaviors). These animal models represent the pathophysiological substrate of REM sleep behavior disorder, a parasomnia in humans characterized by nightmares and abnormal vigorous behaviors (e.g., prominent jerking, shouting, kicking) linked to excessive phasic and/or tonic electromyographic activity in REM sleep. The extraordinary observation that a sleep disorder is often the first manifestation of a devastating neurodegenerative disease such as Parkinson disease carries important diagnostic implications and opens a window for neuroprotection. This review addresses the neuronal substrates of REM sleep generation and modulation and how its impairment may lead to REM sleep behavior disorder.

Diagnostic Criteria, Differential Diagnosis, and Treatment of Minor Motor Activity and Less Well-Known Movement Disorders of Sleep

“…While the most well-known sleep disorders with abnormal motor activity during the night, such as RLS and RBD, are the focus of multiple reviews [ 2 •, 3 •, 4 •, 5 •, 6 , 7 , 8 •, 9 , 10 ], the other motor disorders of sleep are often considered less frequent, less important, or not clinically relevant. This leads to the fact that some of them are frequently missed or misinterpreted in their meaning and implications or confounded in differential diagnosis.…”

Comparing the accuracy and neuroanatomical correlates of the UPSIT-40 and the Sniffin’ Sticks test in REM sleep behavior disorder

“…Exclusion criteria consisted of [1]: Presence of psychiatric and/or neurologic comorbidity [2], MMSE score < 25 [3], claustrophobia [4], MRI artifacts [5], pathological MRI findings other than mild white matter hyperintensities, and [6] exclusion of HC with evidence of a clinical history suggestive of abnormal sleep behaviors and cognitive impairment. Specific exclusion criteria for the olfaction test were: (1) history of nasal bone fracture, (2) diagnosis of rhinitis or nasal polyps, and (3) upper respiratory tract infections in the two weeks prior to testing.…”

“…The Sniffin' Sticks Extended Test (www.burghart-mt.de) consists of three subtests [1]: the Threshold test (Sniffin-Thr) used to ascertain the patient's olfactory threshold. It has 48 Sniffin' Sticks (32 blanks and 16 dilutions of n-butanol) [2]; the Discrimination test (Sniffin-D), where the patient must differentiate between smells with varying degrees of similarity.…”

“…Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by abnormal motor and vocal behaviors associated with unpleasant dreams and increased electromyographic activity during REM sleep [1]. The idiopathic form of RBD (IRBD) is diagnosed when RBD symptomatology occurs in the absence of associated comorbidities or known causing factors.…”

Special issue “Parkinson’s disease”

“…The connection between RBD and the pathological process associated with PD emerged as it gradually became clear that PD involved a very large number of non-nigral subcortical centers, including some of those responsible for the regulation of REM sleep. The author reviews many of these centers and also discusses the debate about the origin of movements in RBD, i.e., the "cortical" vs. the "brainstem" hypothesis (Iranzo 2018). Although no animal model presently exists to prove that following the injection of aggregated recombinant α-synuclein into key REM sleep-related regions clinical RBD develops or the pathology spreads from there to other structures, some preliminary evidence does exist following injection of a recombinant adeno-associated virus expressing human α-synuclein into the REM sleep circuit in mice for the pathological aggregation of Lewy-like pathology in REM sleep-generating cells and for elevated levels of phasic motor activity during REM sleep (McKenna and Peever 2017).…”