Melatonin for rapid eye movement sleep behavior disorder in Parkinson's disease : a randomised controlled trial

Background Melatonin may reduce REM-sleep behavior disorder (RBD) symptoms in Parkinson's disease (PD), though robust clinical trials are lacking. Objective To assess the efficacy of prolonged-release (PR) melatonin for RBD in PD. Methods Randomized, double-blind, placebo-controlled, parallel-group trial with an 8-week intervention and 4-week observation pre- and postintervention (ACTRN12613000648729). Thirty PD patients with rapid eye movement sleep behavior disorder were randomized to 4 mg of prolonged-release melatonin (Circadin) or matched placebo, ingested orally once-daily before bedtime. Primary outcome was the aggregate of rapid eye movement sleep behavior disorder incidents averaged over weeks 5 to 8 of treatment captured by a weekly diary. Data were included in a mixed-model analysis of variance (n = 15 per group). Results No differences between groups at the primary endpoint (3.4 events/week melatonin vs. 3.6 placebo; difference, 0.2; 95% confidence interval = -3.2 to 3.6; P = 0.92). Adverse events included mild headaches, fatigue, and morning sleepiness (n = 4 melatonin; n = 5 placebo). Conclusion Prolonged-release melatonin 4 mg did not reduce rapid eye movement sleep behavior disorder in PD. (c) 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Detection of turning freeze in Parkinson's disease based on S-transform decomposition of EEG signals

© 2017 IEEE. Freezing of Gait (FOG) is a highly debilitating and poorly understood symptom of Parkinson's disease (PD), causing severe immobility and decreased quality of life. Turning Freezing (TF) is known as the most common sub-type of FOG, also causing the highest rate of falls in PD patients. During a TF, the feet of PD patients appear to become stuck whilst making a turn. This paper presents an electroencephalography (EEG) based classification method for detecting turning freezing episodes in six PD patients during Timed Up and Go Task experiments. Since EEG signals have a time-variant nature, time-frequency Stockwell Transform (S-Transform) techniques were used for feature extraction. The EEG sources were separated by means of independent component analysis using entropy bound minimization (ICA-EBM). The distinctive frequency-based features of selected independent components of EEG were extracted and classified using Bayesian Neural Networks. The classification demonstrated a high sensitivity of 84.2%, a specificity of 88.0% and an accuracy of 86.2% for detecting TF. These promising results pave the way for the development of a real-time device for detecting different sub-types of FOG during ambulation

Cognitive training for freezing of gait in Parkinson's disease: a randomized controlled trial.

The pathophysiological mechanism of freezing of gait (FoG) has been linked to executive dysfunction. Cognitive training (CT) is a non-pharmacological intervention which has been shown to improve executive functioning in Parkinson's disease (PD). This study aimed to explore whether targeted CT can reduce the severity of FoG in PD. Patients with PD who self-reported FoG and were free from dementia were randomly allocated to receive either a CT intervention or an active control. Both groups were clinician-facilitated and conducted twice-weekly for seven weeks. The primary outcome was percentage of time spent frozen during a Timed Up and Go task, assessed both on and off dopaminergic medications. Secondary outcomes included multiple neuropsychological and psychosocial measures. A full analysis was first conducted on all participants randomized, followed by a sample of interest including only those who had objective FoG at baseline, and completed the intervention. Sixty-five patients were randomized into the study. The sample of interest included 20 in the CT group and 18 in the active control group. The primary outcome of percentage time spent frozen during a gait task was significantly improved in the CT group compared to active controls in the on-state. There were no differences in the off-state. Patients who received CT also demonstrated improved processing speed and reduced daytime sleepiness compared to those in the active control. The findings suggest that CT can reduce the severity of FoG in the on-state, however replication in a larger sample is required

New Insights into Freezing of Gait in Parkinson's Disease from Spectral Dynamic Causal Modeling

Taniguchi S., Kajiyama Y., Kochiyama T., et al. New Insights into Freezing of Gait in Parkinson's Disease from Spectral Dynamic Causal Modeling. Movement Disorders, (2024); https://doi.org/10.1002/mds.29988.Background: Freezing of gait is one of the most disturbing motor symptoms of Parkinson's disease (PD). However, the effective connectivity between key brain hubs that are associated with the pathophysiological mechanism of freezing of gait remains elusive. Objective: The aim of this study was to identify effective connectivity underlying freezing of gait. Methods: This study applied spectral dynamic causal modeling (DCM) of resting-state functional magnetic resonance imaging in dedicated regions of interest determined using a data-driven approach. Results: Abnormally increased functional connectivity between the bilateral dorsolateral prefrontal cortex (DLPFC) and the bilateral mesencephalic locomotor region (MLR) was identified in freezers compared with nonfreezers. Subsequently, spectral DCM analysis revealed that increased top-down excitatory effective connectivity from the left DLPFC to bilateral MLR and an independent self-inhibitory connectivity within the left DLPFC in freezers versus nonfreezers (>99% posterior probability) were inversely associated with the severity of freezing of gait. The lateralization of these effective connectivity patterns was not attributable to the initial dopaminergic deficit nor to structural changes in these regions. Conclusions: We have identified novel effective connectivity and an independent self-inhibitory connectivity underlying freezing of gait. Our findings imply that modulating the effective connectivity between the left DLPFC and MLR through neurostimulation or other interventions could be a target for reducing freezing of gait in PD

Dopamine depletion impairs gait automaticity by altering cortico-striatal and cerebellar processing in Parkinson's disease

Impairments in motor automaticity cause patients with Parkinson's disease to rely on attentional resources during gait, resulting in greater motor variability and a higher risk of falls. Although dopaminergic circuitry is known to play an important role in motor automaticity, little evidence exists on the neural mechanisms underlying the breakdown of locomotor automaticity in Parkinson's disease. This impedes clinical management and is in great part due to mobility restrictions that accompany the neuroimaging of gait. This study therefore utilized a virtual reality gait paradigm in conjunction with functional MRI to investigate the role of dopaminergic medication on lower limb motor automaticity in 23 patients with Parkinson's disease that were measured both on and off dopaminergic medication. Participants either operated foot pedals to navigate a corridor (‘walk’ condition) or watched the screen while a researcher operated the paradigm from outside the scanner (‘watch’ condition), a setting that controlled for the non-motor aspects of the task. Step time variability during walk was used as a surrogate measure for motor automaticity (where higher variability equates to reduced automaticity), and patients demonstrated a predicted increase in step time variability during the dopaminergic “off” state. During the “off” state, subjects showed an increased blood oxygen level-dependent response in the bilateral orbitofrontal cortices (walk>watch). To estimate step time variability, a parametric modulator was designed that allowed for the examination of brain regions associated with periods of decreased automaticity. This analysis showed that patients on dopaminergic medication recruited the cerebellum during periods of increasing variability, whereas patients off medication instead relied upon cortical regions implicated in cognitive control. Finally, a task-based functional connectivity analysis was conducted to examine the manner in which dopamine modulates large-scale network interactions during gait. A main effect of medication was found for functional connectivity within an attentional motor network and a significant condition by medication interaction for functional connectivity was found within the striatum. Furthermore, functional connectivity within the striatum correlated strongly with increasing step time variability during walk in the off state (r=0.616, p=0.002), but not in the on state (r=−0.233, p=0.284). Post-hoc analyses revealed that functional connectivity in the dopamine depleted state within an orbitofrontal-striatal limbic circuit was correlated with worse step time variability (r=0.653,

Towards closed-loop deep brain stimulation for freezing of gait in Parkinson’s disease

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Exploring the Neural Mechanisms underlying Freezing of Gait in Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1-2% of the elderly population. The majority of PD patients develop freezing of gait (FOG), when they experience a sudden cessation of forward progression of the feet despite the intention to walk. FOG causes frequent falls and impacts on the patient’s mobility and independence. FOG results from pathophysiological mechanisms in the brain that are poorly understood, which makes FOG a particular challenge to treat. The overall aim of this thesis is therefore to improve our understanding of the processes underlying FOG in PD and guide adequate treatment development for this devastating symptom. In particular, the processes underlying key concomitant (i.e. motor automaticity impairments and limbic circuit dysfunctions), provoking (i.e. turning) and alleviating (i.e. sensory cueing) factors are investigated. Developments in the clinical management of FOG are then reviewed to establish a set of recommendations to guide future treatment development. The methodology makes use of a Virtual Reality paradigm (VR) in conjunction with functional Magnetic Resonance Imaging (fMRI). The VR partly overcomes the movement restrictions inherent to fMRI while allowing for the investigation of the neural mechanisms underlying lower limb motor control and sensorimotor feedback. The findings suggest that FOG in PD is associated with functional deficits across the frontal and parietal cortices; the basal ganglia; and the brainstem and cerebellar locomotor regions. It is further recognized that the future management of FOG would require specific neuronal and motoric markers to tailor personalized treatments that can operate in an on-demand manner. It is hoped that the insights gained into the neural circuit deficits underlying FOG and the recommendation of a common approach to advance future treatments will ultimately translate in this thesis into improved treatment strategies for this highly burdensome feature of PD

How to Annotate Freezing of Gait from Video: A Standardized Method Using Open-Source Software

Visually scoring freezing of gait (FOG) from video is increasingly recognized as the gold-standard for assessing FOG severity in Parkinson's disease. Surprisingly, no guidelines exist on how to visually score FOG. Here, I present a free template that can be implemented in open-source software to annotate FOG from video. I provide a user guide on how to implement the template and standardize the scoring of FOG and the percentage of time spent with FOG (% FOG). It is hoped that by disseminating this method investigators will be better able to employ % FOG as an outcome in their studies and therapeutic trials.status: publishe

Non-motor network decoupling accompanies conversion to freezing of gait in Parkinson’s disease

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Bevriezen van het stappen bij de ziekte van Parkinson: van pathofysiologie naar betere behandeling

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