Detection of REM Sleep Behaviour Disorder by Automated Polysomnography Analysis

Evidence suggests Rapid-Eye-Movement (REM) Sleep Behaviour Disorder (RBD) is an early predictor of Parkinson's disease. This study proposes a fully-automated framework for RBD detection consisting of automated sleep staging followed by RBD identification. Analysis was assessed using a limited polysomnography montage from 53 participants with RBD and 53 age-matched healthy controls. Sleep stage classification was achieved using a Random Forest (RF) classifier and 156 features extracted from electroencephalogram (EEG), electrooculogram (EOG) and electromyogram (EMG) channels. For RBD detection, a RF classifier was trained combining established techniques to quantify muscle atonia with additional features that incorporate sleep architecture and the EMG fractal exponent. Automated multi-state sleep staging achieved a 0.62 Cohen's Kappa score. RBD detection accuracy improved by 10% to 96% (compared to individual established metrics) when using manually annotated sleep staging. Accuracy remained high (92%) when using automated sleep staging. This study outperforms established metrics and demonstrates that incorporating sleep architecture and sleep stage transitions can benefit RBD detection. This study also achieved automated sleep staging with a level of accuracy comparable to manual annotation. This study validates a tractable, fully-automated, and sensitive pipeline for RBD identification that could be translated to wearable take-home technology.Comment: 20 pages, 3 figure

Dopamine promotes instrumental motivation, but reduces reward-related vigour.

We can be motivated when reward depends on performance, or merely by the prospect of a guaranteed reward. Performance-dependent (contingent) reward is instrumental, relying on an internal action-outcome model, whereas motivation by guaranteed reward may minimise opportunity cost in reward-rich environments. Competing theories propose that each type of motivation should be dependent on dopaminergic activity. We contrasted these two types of motivation with a rewarded saccade task, in patients with Parkinson's disease (PD). When PD patients were ON dopamine, they had greater response vigour (peak saccadic velocity residuals) for contingent rewards, whereas when PD patients were OFF medication, they had greater vigour for guaranteed rewards. These results support the view that reward expectation and contingency drive distinct motivational processes, and can be dissociated by manipulating dopaminergic activity. We posit that dopamine promotes goal-directed motivation, but dampens reward-driven vigour, contradictory to the prediction that increased tonic dopamine amplifies reward expectation

Investigating gait-responsive somatosensory cueing from a wearable device to improve walking in Parkinson’s disease

Freezing-of-gait (FOG) and impaired walking are common features of Parkinson’s disease (PD). Provision of external stimuli (cueing) can improve gait, however, many cueing methods are simplistic, increase task loading or have limited utility in a real-world setting. Closed-loop (automated) somatosensory cueing systems have the potential to deliver personalised, discrete cues at the appropriate time, without requiring user input. Further development of cue delivery methods and FOG-detection are required to achieve this. In this feasibility study, we aimed to test if FOG-initiated vibration cues applied to the lower-leg via wearable devices can improve gait in PD, and to develop real-time FOG-detection algorithms. 17 participants with Parkinson’s disease and daily FOG were recruited. During 1 h study sessions, participants undertook 4 complex walking circuits, each with a different intervention: continuous rhythmic vibration cueing (CC), responsive cueing (RC; cues initiated by the research team in response to FOG), device worn with no cueing (NC), or no device (ND). Study sessions were grouped into 3 stages/blocks (A-C), separated by a gap of several weeks, enabling improvements to circuit design and the cueing device to be implemented. Video and onboard inertial measurement unit (IMU) data were analyzed for FOG events and gait metrics. RC significantly improved circuit completion times demonstrating improved overall performance across a range of walking activities. Step frequency was significantly enhanced by RC during stages B and C. During stage C, > 10 FOG events were recorded in 45% of participants without cueing (NC), which was significantly reduced by RC. A machine learning framework achieved 83% sensitivity and 80% specificity for FOG detection using IMU data. Together, these data support the feasibility of closed-loop cueing approaches coupling real-time FOG detection with responsive somatosensory lower-leg cueing to improve gait in PD

Two sample Mendelian Randomisation using an outcome from a multilevel model of disease progression

Identifying factors that are causes of disease progression, especially in neurodegenerative diseases, is of considerable interest. Disease progression can be described as a trajectory of outcome over time—for example, a linear trajectory having both an intercept (severity at time zero) and a slope (rate of change). A technique for identifying causal relationships between one exposure and one outcome in observational data whilst avoiding bias due to confounding is two sample Mendelian Randomisation (2SMR). We consider a multivariate approach to 2SMR using a multilevel model for disease progression to estimate the causal effect an exposure has on the intercept and slope. We carry out a simulation study comparing a naïve univariate 2SMR approach to a multivariate 2SMR approach with one exposure that effects both the intercept and slope of an outcome that changes linearly with time since diagnosis. The simulation study results, across six different scenarios, for both approaches were similar with no evidence against a non-zero bias and appropriate coverage of the 95% confidence intervals (for intercept 93.4–96.2% and the slope 94.5–96.0%). The multivariate approach gives a better joint coverage of both the intercept and slope effects. We also apply our method to two Parkinson’s cohorts to examine the effect body mass index has on disease progression. There was no strong evidence that BMI affects disease progression, however the confidence intervals for both intercept and slope were wide

Parkinson's disease subtypes in the Oxford Parkinson disease centre (OPDC) discovery cohort

Background: Within Parkinson’s there is a spectrum of clinical features at presentation which may represent sub-types of the disease. However there is no widely accepted consensus of how best to group patients. Objective: Use a data-driven approach to unravel any heterogeneity in the Parkinson’s phenotype in a well-characterised, population-based incidence cohort. Methods: 769 consecutive patients, with mean disease duration of 1.3 years, were assessed using a broad range of motor, cognitive and non-motor metrics. Multiple imputation was carried out using the chained equations approach to deal with missing data. We used an exploratory and then a confirmatory factor analysis to determine suitable domains to include within our cluster analysis. K-means cluster analysis of the factor scores and all the variables not loading into a factor was used to determine phenotypic subgroups. Results: Our factor analysis found three important factors that were characterised by: psychological well-being features; non-tremor motor features, such as posture and rigidity; and cognitive features. Our subsequent five cluster model identified groups characterised by (1) mild motor and non-motor disease (25.4%), (2) poor posture and cognition (23.3%), (3) severe tremor (20.8%), (4) poor psychological well-being, RBD and sleep (18.9%), and (5) severe motor and non-motor disease with poor psychological well-being (11.7%). Conclusion: Our approach identified several Parkinson’s phenotypic sub-groups driven by largely dopaminergic-resistant features (RBD, impaired cognition and posture, poor psychological well-being) that, in addition to dopaminergic-responsive motor features may be important for studying the aetiology, progression, and medication response of early Parkinson’s

The Mechanisms by Which the Ketone Body D-β-Hydroxybutyrate May Improve the Multiple Cellular Pathologies of Parkinson's Disease

Parkinson's disease, a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, is strongly associated with the death of dopaminergic neurons in the brain's substantia nigra. Although dopamine replacement therapy temporarily helps patients manage their motor symptoms, this current standard of care fails to address the underlying network of pathologies that contribute to the persistent death of dopaminergic neurons. Thus, new treatment approaches are needed that address the underlying pathologies and, thereby, slow or halt the progression of the actual disease. D-β-hydroxybutyrate – a ketone body produced by the liver to support brain function during periods of starvation – may provide an option. Lifestyle interventions that induce endogenous D-β-hydroxybutyrate production, such as caloric restriction and ketogenic diets, are known to increase healthspan and lifespan in animal models and are used to treat neurological disorders. The efficacy of these ketosis-inducing interventions, along with the recent development of commercially available D-β-hydroxybutyrate-based nutritional supplements, should inspire interest in the possibility that D-β-hydroxybutyrate itself exerts neuroprotective effects. This review provides a molecular model to justify the further exploration of such a possibility. Herein, we explore the cellular mechanisms by which the ketone body, D-β-hydroxybutyrate, acting both as a metabolite and as a signaling molecule, could help to prevent the development, or slow the progression of, Parkinson's disease. Specifically, the metabolism of D-β-hydroxybutyrate may help neurons replenish their depleted ATP stores and protect neurons against oxidative damage. As a G-protein-coupled receptor ligand and histone deacetylase inhibitor, D-β-hydroxybutyrate may further protect neurons against energy deficit and oxidative stress, while also decreasing damaging neuroinflammation and death by apoptosis. Restricted to the available evidence, our model relies largely upon the interpretation of data from the separate literatures on the cellular effects of D-β-hydroxybutyrate and on the pathogenesis of Parkinson's disease. Future studies are needed to reveal whether D-β-hydroxybutyrate actually has the potential to serve as an adjunctive nutritional therapy for Parkinson's disease

Finite temperature effects on the collapse of trapped Bose-Fermi mixtures

By using the self-consistent Hartree-Fock-Bogoliubov-Popov theory, we present a detailed study of the mean-field stability of spherically trapped Bose-Fermi mixtures at finite temperature. We find that, by increasing the temperature, the critical particle number of bosons (or fermions) and the critical attractive Bose-Fermi scattering length increase, leading to a significant stabilization of the mixture.Comment: 5 pages, 4 figures; minor changes, proof version, to appear in Phys. Rev. A (Nov. 1, 2003

Temporal orienting in Parkinson's disease

Temporal orienting of attention can affect multiple stages of processing to guide adaptive behaviour. We tested whether temporal expectation in different task contexts is compromised in individuals with Parkinson's disease (PD). In Experiment 1 two temporal-orienting tasks were used: a speeded task emphasizing motor preparation and a non-speeded task emphasizing perceptual discrimination using rapid serial visual presentation. In both tasks, auditory cues indicated the likelihood of a target appearing after a short or long interval. In the speeded-response task, participants used the cues to anticipate an easily detectable target stimulus. In the non-speeded perceptual-discrimination task, participants used the cues to help discriminate a target letter embedded in a stream of letters. Relative to healthy participants, participants with PD did not show altered temporal orienting effects in the speeded-response task. However, they were impaired in using temporal cues to improve perceptual discrimination. In Experiment 2, we tested whether the temporal-orienting deficits in the perceptual-discrimination task depended on the requirement to ignore temporally distracting stimuli. We replicated the impaired temporal orienting for perceptual discrimination in an independent group of individuals with PD, and showed the impairment was abolished when individuals were on their dopaminergic medication. In a task without any distracting letters, however, patients off or on medication benefited normally from temporal orienting cues. Our findings suggest that deficits in temporal orienting in individuals with PD interact with specific task demands, such as the requirement to select target from temporally competing distractors