A critical review of the pharmacological treatment of REM sleep behavior disorder in adults: time for more and larger randomized placebo-controlled trials.

Rapid Eye Movement sleep behavior disorder (RBD) is a parasomnia causing sufferers to physically act out their dreams. These behaviors can disrupt sleep and sometimes lead to injuries in patients and their bed-partners. Clonazepam and melatonin are the first-line pharmacological treatment options for RBD based on direct uncontrolled clinical observations and very limited double-blind placebo-controlled trials. Given the risk for adverse outcomes, especially in older adults, it is of great importance to assess the existing level of evidence for the use of these treatments. In this update, we therefore critically review the clinical and scientific evidence on the pharmacological management of RBD in people aged over 50. We focus on the first-line treatments, and provide an overview of all other alternative pharmacological agents trialed for RBD we could locate as supplementary materials. By amalgamating all clinical observations, our update shows that 66.7% of 1,026 RBD patients reported improvements from clonazepam and 32.9% of 137 RBD patients reported improvements from melatonin treatment on various outcome measures in published accounts. Recently, however, three relatively small randomized placebo-controlled trials did not find these agents to be superior to placebo. Given clonazepam and melatonin are clinically assumed to majorly modify or eliminate RBD in nearly all patients-there is an urgent need to test whether this magnitude of treatment effect remains intact in larger placebo-controlled trials.

Functional MRI to Study Gait Impairment in Parkinson's Disease: a Systematic Review and Exploratory ALE Meta-Analysis.

PURPOSE OF REVIEW: Whilst gait impairment is a main cause for disability in Parkinson's disease (PD), its neural control remains poorly understood. We performed a systematic review and meta-analysis of neuroimaging studies of surrogate features of gait in PD. FINDINGS: Assessing the results from PET or SPECT scans after a period of actual walking as well as fMRI during mental imagery or virtual reality (VR) gait paradigms, we found a varying pattern of gait-related brain activity. Overall, a decrease in activation of the SMA during gait was found in PD compared to elderly controls. In addition, the meta-analysis showed that the most consistent gait-related activation was situated in the cerebellar locomotor region (CLR) in PD. Despite methodological heterogeneity, the combined neuroimaging studies of gait provide new insights into its neural control in PD, suggesting that CLR activation likely serves a compensatory role in locomotion.

Investigating motor initiation and inhibition deficits in patients with Parkinson's disease and freezing of gait using a virtual reality paradigm.

Freezing of gait (FOG) is a common, disabling symptom of Parkinson's disease (PD) that is associated with deficits in motor initiation and inhibition. Understanding of underlying neurobiological mechanisms has been limited by difficulties in eliciting and objectively characterizing such gait phenomena in the clinical setting. However, recent work suggests that virtual reality (VR) techniques might offer the potential to study motor control. This study utilized a VR paradigm to explore deficits in motor initiation and stopping performance, including stop failure in PD patients with (Freezers, 31) and without (Non-Freezers, 23) FOG, and healthy age-matched Controls (15). The VR task required subjects to respond to a series of start and stop cues while navigating a corridor using ankle flexion/extension movements on foot pedals. We found that Freezers experienced slower motor output initiation and more frequent start hesitations (SHs) (initiations greater than twice a subject's usual initiation latency) compared to Non-Freezers and Controls. Freezers also showed more marked inhibitory impairments, taking significantly longer to execute motor inhibition, and experiencing an increased frequency of failed stopping in response to stop cues compared to Non-Freezers and Controls. Stopping impairments were exacerbated by stop cues requiring additional cognitive processing. These results suggest that PD patients with FOG have marked impairments in motor initiation and inhibition that are not prominent in patients without FOG, nor healthy controls. Future work combining such VR paradigms with neuroimaging techniques and intra-operative deep brain recordings may increase our understanding of these phenomena, promoting the development of novel technologies and therapeutic approaches.

Dopaminergic basis for impairments in functional connectivity across subdivisions of the striatum in Parkinson's disease.

The pathological hallmark of Parkinson's disease is the degeneration of dopaminergic nigrostriatal neurons, leading to depletion of striatal dopamine. Recent neuroanatomical work has identified pathways for communication across striatal subdivisions, suggesting that the striatum provides a platform for integration of information across parallel corticostriatal circuits. The aim of this study was to investigate whether dopaminergic dysfunction in Parkinson's disease was associated with impairments in functional connectivity across striatal subdivisions, which could potentially reflect reduced integration across corticostriatal circuits. Utilizing resting-state functional magnetic resonance imaging (fMRI), we analyzed functional connectivity in 39 patients with Parkinson's disease, both "on" and "off" their regular dopaminergic medications, along with 40 age-matched healthy controls. Our results demonstrate widespread impairments in connectivity across subdivisions of the striatum in patients with Parkinson's disease in the "off" state. The administration of dopaminergic medication significantly improved connectivity across striatal subdivisions in Parkinson's disease, implicating dopaminergic deficits in the pathogenesis of impaired striatal interconnectivity. In addition, impaired striatal interconnectivity in the Parkinson's disease "off" state was associated with pathological decoupling of the striatum from the thalamic and sensorimotor (SM) networks. Specifically, we found that although the strength of striatal interconnectivity was positively correlated with both (i) the strength of internal thalamic connectivity, and (ii) the strength of internal SM connectivity, in both healthy controls and the Parkinson's disease "on" state, these relationships were absent in Parkinson's disease when in the "off" state. Taken together our findings emphasize the central role of dopamine in integrated striatal function and the pathological consequences of striatal dopamine denervation in Parkinson's disease.

Variability of Stepping during a Virtual Reality Paradigm in Parkinson's Disease Patients with and without Freezing of Gait.

BACKGROUND: Freezing of gait is a common and debilitating symptom affecting many patients with advanced Parkinson's disease. Although the pathophysiology of freezing of gait is not fully understood, a number of observations regarding the pattern of gait in patients with this symptom have been made. Increased 'Stride Time Variability' has been one of the most robust of these features. In this study we sought to identify whether patients with freezing of gait demonstrated similar fluctuations in their stepping rhythm whilst performing a seated virtual reality gait task that has recently been used to demonstrate the neural correlate of the freezing phenomenon. METHODS: Seventeen patients with freezing and eleven non-freezers performed the virtual reality task twice, once whilst 'On' their regular Parkinsonian medication and once in their practically defined 'Off' state. RESULTS: All patients displayed greater step time variability during their 'Off' state assessment compared to when medicated. Additionally, in the 'Off' state, patients with freezing of gait had greater step time variability compared to non-freezers. The five steps leading up to a freezing episode in the virtual reality environment showed a significant increase in step time variability although the final three steps preceding the freeze were not characterized by a progressive shortening of latency. CONCLUSIONS: The results of this study suggest that characteristic features of gait disturbance observed in patients with freezing of gait can also be demonstrated with a virtual reality paradigm. These findings suggest that virtual reality may offer the potential to further explore the freezing phenomenon in Parkinson's disease.