Altered resting-state thalamo-occipital functional connectivity is associated with cognition in isolated rapid eye movement sleep behavior disorder.

OBJECTIVE: Isolated rapid eye movement sleep behavior disorder (iRBD) patients are at risk of cognitive impairments, however the underlying mechanism is still unclear. This study aimed to evaluate thalamo-cortical functional connectivity (FC) using resting-state functional magnetic resonance imaging (fMRI) and its correlation with cognitive dysfunction in patients with iRBD. METHODS: A total 37 polysomnographies (PSGs) confirmed iRBD patients and 15 age-sex matched controls underwent resting-state fMRI and comprehensive neuropsychological assessment. Thalamo-cortical FC was evaluated by using seed-to voxel analysis and was compared between the iRBD and controls. Correlation between the average value of significant clusters and cognitive function scores in iRBD were calculated. RESULTS: Compared to the control subjects, patients with iRBD patients showed cognitive decline in word list recognition (p = 0.016), and constructional recall (p = 0.044). The FC analysis showed increased FC between the left thalamus and occipital regions including the right cuneal cortex, left fusiform gyrus and lingual gyrus (cluster level p < 0.05, corrected for false discovery rate). The averaged thalamo-fusiform FC value positively correlated with word list recognition after adjusting for age and sex (adjusted r = 0.347, p = 0.041). CONCLUSION: Thalamic resting state FC is altered in iRBD patients and is associated with the cognitive function. Enhancement of the thalamo-occipital FC may reflect a compensatory mechanism for cognitive impairment in iRBD.

Brain atrophy in Parkinson's disease with polysomnography-confirmed REM sleep behavior disorder.

We aimed to investigate cortical and subcortical brain alterations in people with Parkinson's disease with polysomnography-confirmed rapid eye movement (REM) sleep behavior disorder (RBD). Thirty people with Parkinson's disease, including 15 people with RBD, were recruited and compared with 41 healthy controls. Surface-based cortical and subcortical analyses were performed on T1-weighted images to investigate thickness and shape abnormalities between groups, and voxel-based and deformation-based morphometry were performed to investigate local volume. Correlations were performed in patients to investigate the structural correlates of motor activity during REM sleep. People with RBD showed cortical thinning in the right perisylvian and inferior temporal cortices and shape contraction in the putamen compared with people without RBD. Compared with controls, people with RBD had extensive cortical thinning and volume loss, brainstem volume was reduced, and shape contraction was found in the basal ganglia and hippocampus. In comparison to controls, people without RBD showed more restricted thinning in the sensorimotor, parietal, and occipital cortices, reduced volume in the brainstem, temporal and more posterior areas, and shape contraction in the pallidum and hippocampus. In Parkinson's disease, higher tonic and phasic REM sleep motor activity was associated with contraction of the thalamic surface, extensive cortical thinning, and subtle volume reduction in the middle temporal gyrus. In Parkinson's disease, the presence of RBD is associated with extensive cortical and subcortical abnormalities, suggesting more severe neurodegeneration in people with RBD. This provides potential neuroanatomical correlates for the more severe clinical phenotype reported in people with Parkinson's disease with RBD.

Extrastriatal monoaminergic dysfunction and enhanced microglial activation in idiopathic rapid eye movement sleep behaviour disorder.

BACKGROUND: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. METHODS: We studied twenty-one polysomnography-confirmed iRBD patients with 18F-DOPA and 11C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 9 18F-DOPA and n = 20 11C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. RESULTS: Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of 18F-DOPA Ki values compared to controls (mean difference = -0.00026, 95% confidence interval [-0.00050 to -0.00002], p-value = 0.03). No associated thalamic changes in 11C-PK11195 binding were observed. Other regions sampled showed no 18F-DOPA or 11C-PK11195 PET differences between groups. Voxel-level interrogation of 11C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. CONCLUSION: Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction.

Increased dopaminergic function in the thalamus is associated with excessive daytime sleepiness.

OBJECTIVES/BACKGROUND: Excessive daytime sleepiness (EDS) is a common disorder, which can manifest in isolation or in combination with other neurological or psychiatric disorders. We know relatively little about the mechanisms underlying the development of EDS and the clinical management of patients with EDS remains an unmet need. In this study, we hypothesised that thalamic dopaminergic function would be altered in subjects with EDS and we sought to investigate this by assessing [123I]FP-CIT Single Photon Emission Computed Tomography (SPECT) data, which is a molecular imaging marker of dopamine transporter (DAT). PATIENTS/METHODS: We performed a case-control study using people registered as healthy subjects in the Parkinson's Progression Markers Initiative database. We assessed and compared semi-quantified [123I]FP-CIT-SPECT in two groups of 21 healthy subjects with and without EDS, who were matched for age, gender, years of education and Rapid eyemovement (REM) sleep behaviour disorder (RBD) Questionnaire scores. RESULTS: Our findings show increased thalamic DAT binding in people with EDS compared to matched healthy subjects without EDS. Higher thalamic DAT binding also correlated with worse EDS scores. CONCLUSION: Our findings provide evidence that increased dopaminergic function in the thalamus may mediate excessive daytime sleepiness in humans.

Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder.

Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in muscle atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients.

Loss of Substantia Nigra Hyperintensity at 3.0-T MR Imaging in Idiopathic REM Sleep Behavior Disorder: Comparison with 123I-FP-CIT SPECT.

Purpose To examine whether the loss of nigral hyperintensity (NH) on 3.0-T susceptibility-weighted (SW) magnetic resonance (MR) images can help identify high synucleinopathy risk in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). Materials and Methods Between March 2014 and April 2015, 18 consecutively recruited patients with iRBD were evaluated with 3.0-T SW imaging and iodine 123-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT) single photon emission computed tomography and compared with 18 healthy subjects and 18 patients with Parkinson disease (PD). Two readers blinded to clinical diagnosis independently assessed the images. 123I-FP-CIT uptake ratios were compared by using the Kruskal-Wallis test, and intra- and interobserver agreements were assessed with the Cohen κ. The synucleinopathy conversion according to NH status was evaluated in patients with iRBD after follow-up. Results NH was intact in seven patients with iRBD and lost in 11. The 123I-FP-CIT uptake ratios were comparable between those with intact NH (mean, 3.22 ± 0.47) and healthy subjects (mean, 3.37 ± 0.47) (P = .495). The 123I-FP-CIT uptake ratios in the 11 patients with iRBD and NH loss (mean, 2.48 ± 0.44) were significantly lower than those in healthy subjects (mean, 3.37 ± 0.47; P < .001) but higher than those in patients with PD (mean, 1.80 ± 0.33; P < .001). The intra- and interobserver agreements were excellent (κ > 0.9). Five patients with iRBD and NH loss developed symptoms of parkinsonism or dementia 18 months after neuroimaging. Conclusion NH loss at 3.0-T SW imaging may be a promising marker for short-term synucleinopathy risk in iRBD. © RSNA, 2017 Online supplemental material is available for this article.

Effect of low-intensity pure tone auditory stimulation on patients with rapid eye movement sleep behavior disorder.

OBJECTIVE: This study aimed to investigate the influence of low-intensity pure tone auditory stimulation on patients with rapid eye movement (REM), sleep behavior disorder (RBD), and attempt to identify a new method of RBD intervention. METHODS: Patients diagnosed with idiopathic RBD (iRBD) or symptomatic RBD (sRBD) were given auditory stimulation of low-intensity pure tones during their REM sleep. Sleep parameters including sleep process, sleep architecture as well as eye movements (EMs) frequency, and amplitude were recorded by polysomnography monitoring at pre-, intra-, and post-stimulation. RESULTS: Thirteen iRBD and 18 sRBD patients completed this study. Auditory stimulation significantly reduced the EMs frequency and amplitude in iRBD and sRBD patients (p < 0.05). In the iRBD group, the intra-stimulated FSL increased significantly than the pre-stimulated FSL (p < 0.05). After stimulation, patients had similar sleep latency (FSL), rapid eye movement sleep latency (RSL) and periodic limb movements in sleep (PLMS) compared with control. In the sRBD group, the intra-stimulated total sleep time, sleep efficiency was significantly increased, whereas the RSL and PLMS were significantly reduced compared with the pre-stimulated ones (all p < 0.05). The sRBD patients had similar time in bed, FSL and RBD episodes compared with control (all p < 0.05) in spite of significant difference before stimulation (all p < 0.05). However, the sleep architecture was not influenced by the stimulation despite the decrease in N3% in iRBD group (p < 0.05). CONCLUSION: Low-intensity pure tone auditory stimulation may be a potentially effective intervention for RBD, especially for sRBD.

Wilson's disease with and without rapid eye movement sleep behavior disorder compared to healthy matched controls.

OBJECTIVE: Quantitative data are reported on rapid eye movement (REM) sleep behavior disorder (RBD) in a cohort of predominantly neurological Wilson's disease (WD). METHODS: A total of 41 patients with WD and 41 healthy, age- and gender-matched controls were studied by conducting face-to-face interviews, neurological and clinical examinations, laboratory tests, and WD- and RBD-specific scales. Video-polysomnography and quantification of REM sleep without atonia (RWA) were conducted in 35 patients and 41 controls. RESULTS: Patients with WD showed significantly worse sleep quality, less sleep efficiency, increased wakefulness after sleep onset, and more arousals compared to healthy controls. Five patients with WD (four women) fulfilled the diagnostic criteria for RBD with significantly higher values in RWA, RBD Questionnaire-Hong Kong, and RBD Screening Questionnaire compared to patients with WD without RBD. In three patients with WD, RBD had manifested before any other symptom that could be attributed to WD. Percentage of RWA was significantly lower in WD without RBD than in WD with RBD, but still significantly increased compared to controls. CONCLUSIONS: RBD can be comorbid with WD. RWA is commonly present in WD, both in the presence or absence of clinical RBD. A causal connection is possible, though retrospective determination of RBD onset and the low number of patients do not allow a definitive conclusion at this point. However, screening for WD in idiopathic RBD is available at low cost and is recommended. Early-stage copper chelation therapy provides a highly effective treatment to prevent further WD manifestations and might also control the comorbid RBD.

Mechanisms of REM sleep in health and disease.

PURPOSE OF REVIEW: Our understanding of rapid eye movement (REM) sleep and how it is generated remains a topic of debate. Understanding REM sleep mechanisms is important because several sleep disorders result from disturbances in the neural circuits that control REM sleep and its characteristics. This review highlights recent work concerning how the central nervous system regulates REM sleep, and how the make up and breakdown of these REM sleep-generating circuits contribute to narcolepsy, REM sleep behaviour disorder and sleep apnea. RECENT FINDINGS: A complex interaction between brainstem REM sleep core circuits and forebrain and hypothalamic structures is necessary to generate REM sleep. Cholinergic activation and GABAergic inhibition trigger the activation of subcoeruleus neurons, which form the core of the REM sleep circuit. SUMMARY: Untimely activation of REM sleep circuits leads to cataplexy - involuntary muscle weakness or paralysis - a major symptom of narcolepsy. Degeneration of the REM circuit is associated with excessive muscle activation in REM sleep behaviour disorder. Inappropriate arousal from sleep during obstructive sleep apnea repeatedly disturbs the activity of sleep circuits, particularly the REM sleep circuit.

Sensorimotor gating deficits in multiple system atrophy: comparison with Parkinson's disease and idiopathic REM sleep behavior disorder.

BACKGROUND: Prepulse inhibition (PPI) of the auditory blink reflex is a measure of sensorimotor gating, which reflects an organism's ability to filter out irrelevant sensory information. PPI has never been studied in patients with multiple system atrophy (MSA), although sensorimotor deficits are frequently associated with synucleinopathies. We investigated whether alterations in PPI were more pronounced in MSA compared with Parkinson's disease (PD), idiopathic rapid eye movement sleep behavior disorder (iRBD) and healthy controls. METHODS: 10 patients with MSA, 12 patients with iRBD, 40 patients with PD, and 20 healthy controls completed the study. A passive acoustic prepulse inhibition paradigm was applied with prepulses 5 dB and 15 dB above background noise at 30-, 60-, 120- and 300-ms intervals. RESULTS: Non-parametric analyses showed that MSA patients had significantly lower prepulse inhibition, as measured with max-amplitude, than PD patients and iRBD patients on the 60 ms-85 dB and 120 ms-85 dB inter-stimulus intervals. The same relation was found when using area under the curve. No differences were found between groups for the 30 ms-85 dB and 300 ms-85 dB. Furthermore, blink reflex characteristics such as habituation did not differ between patients and controls. CONCLUSIONS: The present study showed that sensorimotor gating, as measured with PPI, is markedly reduced in MSA. This may be due to the pronounced severity of striatal and brainstem dysfunction, as well as the degeneration of other structures related to the PPI modulating pathways in MSA. PPI may be a non-invasive neurophysiological measure that can aid in the differential diagnosis between PD and MSA.

Decreased sleep spindle density in patients with idiopathic REM sleep behavior disorder and patients with Parkinson's disease.

OBJECTIVE: To determine whether sleep spindles (SS) are potentially a biomarker for Parkinson's disease (PD). METHODS: Fifteen PD patients with REM sleep behavior disorder (PD+RBD), 15 PD patients without RBD (PD-RBD), 15 idiopathic RBD (iRBD) patients and 15 age-matched controls underwent polysomnography (PSG). SS were scored in an extract of data from control subjects. An automatic SS detector using a Matching Pursuit (MP) algorithm and a Support Vector Machine (SVM) was developed and applied to the PSG recordings. The SS densities in N1, N2, N3, all NREM combined and REM sleep were obtained and evaluated across the groups. RESULTS: The SS detector achieved a sensitivity of 84.7% and a specificity of 84.5%. At a significance level of α=1%, the iRBD and PD+RBD patients had a significantly lower SS density than the control group in N2, N3 and all NREM stages combined. At a significance level of α=5%, PD-RBD had a significantly lower SS density in N2 and all NREM stages combined. CONCLUSIONS: The lower SS density suggests involvement in pre-thalamic fibers involved in SS generation. SS density is a potential early PD biomarker. SIGNIFICANCE: It is likely that an automatic SS detector could be a supportive diagnostic tool in the evaluation of iRBD and PD patients.

New aspects in the pathophysiology of rapid eye movement sleep behavior disorder: the potential role of glutamate, gamma-aminobutyric acid, and glycine.

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by the occurrence of intense movements during rapid eye movement (REM) sleep, also named paradoxical sleep. The neuronal dysfunctions at the origin of the loss of atonia in RBD patients are not known. One possibility is that RBD is due to the degeneration of neurons inducing the muscle atonia of REM sleep. Therefore, in our paper we review data on the populations of neurons responsible for the atonia of REM sleep before discussing their potential role in RBD. We first review evidence that motoneurons are tonically hyperpolarized by gamma-aminobutyric acid (GABA) and glycine and phasically excited by glutamate during REM sleep. Then, we review data indicating that the atonia of REM sleep is induced by glycinergic/GABAergic REM-on premotoneurons contained within the raphe magnus and the ventral and alpha gigantocellular reticular nuclei localized in the ventral medullary reticular formation. These neurons are excited during REM sleep by a direct projection from glutamatergic REM-on neurons localized in the pontine sublaterodorsal tegmental nucleus (SLD). From these results, we discuss the possibility that RBD is due to a specific degeneration of descending REM-on glutamatergic neurons localized in the caudal SLD or that of the REM-on GABA/glycinergic premotoneurons localized in the ventral medullary reticular formation. We then propose that movements of RBD are induced by descending projections of cortical motor neurons before discussing possible modes of action of clonazepam and melatonin.

Hallucinations and REM sleep behaviour disorder in Parkinson's disease: dream imagery intrusions and other hypotheses.

REM sleep behaviour disorder (RBD) is a REM sleep-related parasomnia which may be considered a "dissociated state of wakefulness and sleep", given that conflicting elements of REM sleep (dreaming) and of wakefulness (sustained muscle tone and movements) coexist during the episodes, leading to motor and behavioural manifestations reminiscent of an enacted dream. RBD has been reported in association with α-synucleinopathies: around a third of patients with Parkinson's disease (PD) have full-blown RBD. Recent data indicate that PD patients with RBD are more prone to hallucinations than PD patients without this parasomnia. However it is still not clear why RBD in PD is associated with an increased prevalence of VHs. Data exist which suggest that visual hallucinations in PD may be the result of untimely intrusions of REM visual imagery into wakefulness. RBD, which is characterised by a REM sleep dissociation pattern, might be a condition that particularly favours such intrusions. However, other hypotheses may be advanced. In fact, deficits in attentional, executive, visuoperceptual and visuospatial abilities have been documented in RBD and found to occur far more frequently in PD with RBD than in PD without RBD. Neuropsychological deficits involving visual perception and attentional processes are thought to play an important role in the pathophysiology of VHs. On this basis, RBD in PD could be viewed as a contributory risk factor for VHs.

The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during paradoxical (REM) sleep (PS). Conversely, cataplexy, one of the key symptoms of narcolepsy, is a striking sudden episode of muscle weakness triggered by emotions during wakefulness, and comparable to REM sleep atonia. The neuronal dysfunctions responsible for RBD and cataplexy are not known. In the present review, we present the most recent results on the neuronal network responsible for PS. Based on these results, we propose an updated integrated model of the mechanisms responsible for PS and explore different hypotheses explaining RBD and cataplexy. We propose that RBD is due to a specific degeneration of a sub-population of PS-on glutamatergic neurons specifically responsible of muscle atonia, localized in the caudal pontine sublaterodorsal tegmental nucleus (SLD). Another possibility is the occurrence in RBD patients of a specific lesion of the glycinergic/GABAergic pre-motoneurons localized in the medullary ventral gigantocellular reticular nucleus. Conversely, cataplexy in narcoleptics would be due to the activation during waking of the caudal PS-on SLD neurons responsible for muscle atonia. A phasic glutamatergic excitatory pathway from the central amygdala to the SLD PS-on neurons activated during emotion would induce such activation. In normal conditions, the glutamate excitation would be blocked by the simultaneous excitation by the hypocretins of the PS-off GABAergic neurons localized in the ventrolateral periaqueductal gray and the adjacent deep mesencephalic reticular nucleus, gating the activation of the PS-on SLD neurons.

Diffuse occipital hypometabolism on [18 F]-FDG PET scans in patients with idiopathic REM sleep behavior disorder: prodromal dementia with Lewy bodies?

BACKGROUND: Previous longitudinal studies have revealed that specific patterns on [(18) F]-fluoro-d-glucose (FDG) positron emission tomography (PET) scans in patients with amnesic mild cognitive impairment can predict Alzheimer's disease (AD). However, the significance of particular patterns on [(18) F]-FDG PET scans in prodromal patients with dementia with Lewy bodies (DLB) remains unclear. METHODS: Based on the prevailing evidence that rapid eye movement (REM) sleep behavior disorder (RBD) often precedes the onset of DLB, [(18) F]-FDG PET scans of nine non-demented patients reporting recurrent nocturnal dream-enactment behavior in our memory clinic were compared with the normative database using three-dimensional stereotactic surface projection (3D-SSP) images. All patients underwent clinical and neuropsychological examinations as well as cardiac [(123) I]-metaiodobenzylguanidine ([(123) I]-MIBG) scintigraphy. RESULTS: Four patients were found to have diffuse areas of reduced cerebral metabolic rate of glucose (CMRglc), predominantly in the occipital lobe, which is the preferentially affected region in DLB patients. In contrast, five patients showed no such occipital hypometabolism; instead, these five patients showed hypometabolism in the left anterior cingulate gyrus (Broadmann area (BA) 24), right frontal lobe (BA 32) and right anterior temporal lobe (BA 38), which are the preferentially affected regions in Parkinson's disease rather than DLB. The extent of the reduction in CMRglc in the left occipital lobe was correlated with scores on the Bender Gestalt Test, which reflects visuospatial ability, but not with global cognitive measures. All patients showed reduced cardiac [(123) I]-MIBG levels, consistent with underlying Lewy body disease. CONCLUSION: These variations in [(18) F]-FDG PET scans raise the possibility that the specific pattern of CMRglc reduction may predict developing DLB in patients with idiopathic RBD. Further follow-up studies are needed, particularly on patients with diffuse occipital hypometabolism.

The implication of nigrostriatal dopaminergic degeneration in the pathogenesis of REM sleep behavior disorder.

BACKGROUND AND PURPOSE: The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is not clear despite its frequent association with Parkinson's disease (PD). We investigated whether the nigrostriatal dopaminergic system is involved in the development of idiopathic RBD. METHODS: Fourteen patients with RBD, 14 patients with PD and 12 normal controls were included in the study. The diagnosis of RBD was confirmed on polysomnography. All the participants performed single-photon emission computed tomography imaging 3 h after injection of [(123)I]FP-CIT. During REM sleep of the RBD patients, each 30-s epoch was rated as 'tonic' when there was at least 50% of tonically maintained chin electromyography (EMG) activity in the epoch. Phasic EMG activities were calculated as the percentage of 3-s mini-epoch containing phasic EMG events (leg and chin, separately). RESULTS: The RBD patients showed a trend of lower binding in the striatum than the normal controls (P = 0.07), and the significance was revealed in the putamen (P = 0.02). However, in 11 individual cases of the 14 RBD patients, the dopamine transporter (DAT) densities in the putamen still remained within the normal range. In the RBD patients, there was no correlation between EMG activities and DAT densities. CONCLUSIONS: Nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. The lack of correlation between RBD severity and DAT densities suggests that another pathogenic process not related to nigrostriatal dopaminergic transmission may be implicated in RBD.