Progression subtypes in Parkinson's disease identified by a data-driven multi cohort analysis.

The progression of Parkinson's disease (PD) is heterogeneous across patients, affecting counseling and inflating the number of patients needed to test potential neuroprotective treatments. Moreover, disease subtypes might require different therapies. This work uses a data-driven approach to investigate how observed heterogeneity in PD can be explained by the existence of distinct PD progression subtypes. To derive stable PD progression subtypes in an unbiased manner, we analyzed multimodal longitudinal data from three large PD cohorts and performed extensive cross-cohort validation. A latent time joint mixed-effects model (LTJMM) was used to align patients on a common disease timescale. Progression subtypes were identified by variational deep embedding with recurrence (VaDER). In each cohort, we identified a fast-progressing and a slow-progressing subtype, reflected by different patterns of motor and non-motor symptoms progression, survival rates, treatment response, features extracted from DaTSCAN imaging and digital gait assessments, education, and Alzheimer's disease pathology. Progression subtypes could be predicted with ROC-AUC up to 0.79 for individual patients when a one-year observation period was used for model training. Simulations demonstrated that enriching clinical trials with fast-progressing patients based on these predictions can reduce the required cohort size by 43%. Our results show that heterogeneity in PD can be explained by two distinct subtypes of PD progression that are stable across cohorts. These subtypes align with the brain-first vs. body-first concept, which potentially provides a biological explanation for subtype differences. Our predictive models will enable clinical trials with significantly lower sample sizes by enriching fast-progressing patients.

Overground Walking With a Transparent Exoskeleton Shows Changes in Spatiotemporal Gait Parameters.

Lower-limb gait training (GT) exoskeletons have been successfully used in rehabilitation programs to overcome the burden of locomotor impairment. However, providing suitable net interaction torques to assist patient movements is still a challenge. Previous transparent operation approaches have been tested in treadmill-based GT exoskeletons to improve user-robot interaction. However, it is not yet clear how a transparent lower-limb GT system affects user's gait kinematics during overground walking, which unlike treadmill-based systems, requires active participation of the subjects to maintain stability. In this study, we implemented a transparent operation strategy on the ExoRoboWalker, an overground GT exoskeleton, to investigate its effect on the user's gait. The approach employs a feedback zero-torque controller with feedforward compensation for the exoskeleton's dynamics and actuators' impedance. We analyzed the data of five healthy subjects walking overground with the exoskeleton in transparent mode (ExoTransp) and non-transparent mode (ExoOff) and walking without exoskeleton (NoExo). The transparent controller reduced the user-robot interaction torque and improved the user's gait kinematics relative to ExoOff. No significant difference in stride length is observed between ExoTransp and NoExo (p = 0.129). However, the subjects showed a significant difference in cadence between ExoTransp (50.9± 1.1 steps/min) and NoExo (93.7 ± 8.7 steps/min) (p = 0.015), but not between ExoTransp and ExoOff (p = 0.644). Results suggest that subjects wearing the exoskeleton adjust their gait as in an attention-demanding task changing the spatiotemporal gait characteristics likely to improve gait balance.

Luxembourg Parkinson's study -comprehensive baseline analysis of Parkinson's disease and atypical parkinsonism.

Background: Deep phenotyping of Parkinson's disease (PD) is essential to investigate this fastest-growing neurodegenerative disorder. Since 2015, over 800 individuals with PD and atypical parkinsonism along with more than 800 control subjects have been recruited in the frame of the observational, monocentric, nation-wide, longitudinal-prospective Luxembourg Parkinson's study. Objective: To profile the baseline dataset and to explore risk factors, comorbidities and clinical profiles associated with PD, atypical parkinsonism and controls. Methods: Epidemiological and clinical characteristics of all 1,648 participants divided in disease and control groups were investigated. Then, a cross-sectional group comparison was performed between the three largest groups: PD, progressive supranuclear palsy (PSP) and controls. Subsequently, multiple linear and logistic regression models were fitted adjusting for confounders. Results: The mean (SD) age at onset (AAO) of PD was 62.3 (11.8) years with 15% early onset (AAO < 50 years), mean disease duration 4.90 (5.16) years, male sex 66.5% and mean MDS-UPDRS III 35.2 (16.3). For PSP, the respective values were: 67.6 (8.2) years, all PSP with AAO > 50 years, 2.80 (2.62) years, 62.7% and 53.3 (19.5). The highest frequency of hyposmia was detected in PD followed by PSP and controls (72.9%; 53.2%; 14.7%), challenging the use of hyposmia as discriminating feature in PD vs. PSP. Alcohol abstinence was significantly higher in PD than controls (17.6 vs. 12.9%, p = 0.003). Conclusion: Luxembourg Parkinson's study constitutes a valuable resource to strengthen the understanding of complex traits in the aforementioned neurodegenerative disorders. It corroborated several previously observed clinical profiles, and provided insight on frequency of hyposmia in PSP and dietary habits, such as alcohol abstinence in PD.Clinical trial registration: clinicaltrials.gov, NCT05266872.

Crowdsourcing digital health measures to predict Parkinson's disease severity: the Parkinson's Disease Digital Biomarker DREAM Challenge.

Consumer wearables and sensors are a rich source of data about patients' daily disease and symptom burden, particularly in the case of movement disorders like Parkinson's disease (PD). However, interpreting these complex data into so-called digital biomarkers requires complicated analytical approaches, and validating these biomarkers requires sufficient data and unbiased evaluation methods. Here we describe the use of crowdsourcing to specifically evaluate and benchmark features derived from accelerometer and gyroscope data in two different datasets to predict the presence of PD and severity of three PD symptoms: tremor, dyskinesia, and bradykinesia. Forty teams from around the world submitted features, and achieved drastically improved predictive performance for PD status (best AUROC = 0.87), as well as tremor- (best AUPR = 0.75), dyskinesia- (best AUPR = 0.48) and bradykinesia-severity (best AUPR = 0.95).

Accelerometer data collected with a minimum set of wearable sensors from subjects with Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder associated with motor and non-motor symptoms. Current treatments primarily focus on managing motor symptom severity such as tremor, bradykinesia, and rigidity. However, as the disease progresses, treatment side-effects can emerge such as on/off periods and dyskinesia. The objective of the Levodopa Response Study was to identify whether wearable sensor data can be used to objectively quantify symptom severity in individuals with PD exhibiting motor fluctuations. Thirty-one subjects with PD were recruited from 2 sites to participate in a 4-day study. Data was collected using 2 wrist-worn accelerometers and a waist-worn smartphone. During Days 1 and 4, a portion of the data was collected in the laboratory while subjects performed a battery of motor tasks as clinicians rated symptom severity. The remaining of the recordings were performed in the home and community settings. To our knowledge, this is the first dataset collected using wearable accelerometers with specific focus on individuals with PD experiencing motor fluctuations that is made available via an open data repository.

Limb and trunk accelerometer data collected with wearable sensors from subjects with Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Dyskinesia and motor fluctuations are complications of PD medications. An objective measure of on/off time with/without dyskinesia has been sought for some time because it would facilitate the titration of medications. The objective of the dataset herein presented is to assess if wearable sensor data can be used to generate accurate estimates of limb-specific symptom severity. Nineteen subjects with PD experiencing motor fluctuations were asked to wear a total of five wearable sensors on both forearms and shanks, as well as on the lower back. Accelerometer data was collected for four days, including two laboratory visits lasting 3 to 4 hours each while the remainder of the time was spent at home and in the community. During the laboratory visits, subjects performed a battery of motor tasks while clinicians rated limb-specific symptom severity. At home, subjects were instructed to use a smartphone app that guided the periodic performance of a set of motor tasks.

Assessing the Feasibility of Augmenting Fall Detection Systems by Relying on UWB-Based Position Tracking and a Home Robot.

Falls in the home environment are a primary cause of injury in older adults. According to the U.S. Centers for Disease Control and Prevention, every year, one in four adults 65 years of age and older reports experiencing a fall. A variety of different technologies have been proposed to detect fall events. However, the need to detect all fall instances (i.e., to avoid false negatives) has led to the development of systems marked by high sensitivity and hence a significant number of false alarms. The occurrence of false alarms causes frequent and unnecessary calls to emergency response centers, which are critical resources that should be utilized only when necessary. Besides, false alarms decrease the level of confidence of end-users in the fall detection system with a negative impact on their compliance with using the system (e.g., wearing the sensor enabling the detection of fall events). Herein, we present a novel approach aimed to augment traditional fall detection systems that rely on wearable sensors and fall detection algorithms. The proposed approach utilizes a UWB-based tracking system and a home robot. When the fall detection system generates an alarm, the alarm is relayed to a base station that utilizes a UWB-based tracking system to identify where the older adult and the robot are so as to enable navigating the environment using the robot and reaching the older adult to check if he/she experienced a fall. This approach prevents unnecessary calls to emergency response centers while enabling a tele-presence using the robot when appropriate. In this paper, we report the results of a novel fall detection algorithm, the characteristics of the alarm notification system, and the accuracy of the UWB-based tracking system that we implemented. The fall detection algorithm displayed a sensitivity of 99.0% and a specificity of 97.8%. The alarm notification system relayed all simulated alarm notification instances with a maximum delay of 106 ms. The UWB-based tracking system was found to be suitable to locate radio tags both in line-of-sight and in no-line-of-sight conditions. This result was obtained by using a machine learning-based algorithm that we developed to detect and compensate for the multipath effect in no-line-of-sight conditions. When using this algorithm, the error affecting the estimated position of the radio tags was smaller than 0.2 m, which is satisfactory for the application at hand.

Can mHealth Technology Help Mitigate the Effects of the COVID-19 Pandemic?

Goal: The aim of the study herein reported was to review mobile health (mHealth) technologies and explore their use to monitor and mitigate the effects of the COVID-19 pandemic. Methods: A Task Force was assembled by recruiting individuals with expertise in electronic Patient-Reported Outcomes (ePRO), wearable sensors, and digital contact tracing technologies. Its members collected and discussed available information and summarized it in a series of reports. Results: The Task Force identified technologies that could be deployed in response to the COVID-19 pandemic and would likely be suitable for future pandemics. Criteria for their evaluation were agreed upon and applied to these systems. Conclusions: mHealth technologies are viable options to monitor COVID-19 patients and be used to predict symptom escalation for earlier intervention. These technologies could also be utilized to monitor individuals who are presumed non-infected and enable prediction of exposure to SARS-CoV-2, thus facilitating the prioritization of diagnostic testing.

Development of a "transparent operation mode" for a lower-limb exoskeleton designed for children with cerebral palsy.

Robot-assisted rehabilitation in children and young adults with Cerebral Palsy (CP) is expected to lead to neuroplasticity and reduce the burden of motor impairments. For a lower-limb exoskeleton to perform well in this context, it is essential that the robot be "transparent" to the user and produce torques only when voluntarily-generated motor outputs deviate significantly from the target trajectory. However, the development of transparent operation modes and assistance-as-need control schema are still open problems with several implementation challenges. This paper presents a theoretical approach and provides a discussion of the key issues pertinent to designing a transparent operation mode for a lower-limb exoskeleton suitable for children and young adults with CP. Based on the dynamics of exoskeletons as well as friction models and human-robot interaction models, we propose a control strategy aimed to minimize human-machine interaction forces when subjects generate motor outputs that match the target trajectory. The material is presented as a conceptual framework that can be generalized to other exoskeleton systems for overground walking.

Assessing aberrant muscle activity patterns via the analysis of surface EMG data collected during a functional evaluation.

BACKGROUND: Surface electromyographic (EMG) recordings collected during the performance of functional evaluations allow clinicians to assess aberrant patterns of muscle activity associated with musculoskeletal disorders. This assessment is typically achieved via visual inspection of the surface EMG data. This approach is time-consuming and leads to accurate results only when the assessment is carried out by an EMG expert. METHODS: A set of algorithms was developed to automatically evaluate aberrant patterns of muscle activity. EMG recordings collected during the performance of functional evaluations in 62 subjects (22 to 61 years old) were used to develop and characterize the algorithms. Clinical scores were generated via visual inspection by an EMG expert using an ordinal scale capturing the severity of aberrant patterns of muscle activity. The algorithms were used in a case study (i.e. the evaluation of a subject with persistent back pain following instrumented lumbar fusion who underwent lumbar hardware removal) to assess the clinical suitability of the proposed technique. RESULTS: The EMG-based algorithms produced accurate estimates of the clinical scores. Results were primarily obtained using a linear regression approach. However, when the results were not satisfactory, a regression implementation of a Random Forest was utilized, and the results compared with those obtained using a linear regression approach. The root-mean-square error of the clinical score estimates produced by the algorithms was a small fraction of the ordinal scale used to rate the severity of the aberrant patterns of muscle activity. Regression coefficients and associated 95% confidence intervals showed that the EMG-based estimates fit well the clinical scores generated by the EMG expert. When applied to the clinical case study, the algorithms appeared to capture the characteristics of the muscle activity patterns associated with persistent back pain following instrumented lumbar fusion. CONCLUSIONS: The proposed approach relies on EMG-based measures to generate accurate estimates of the severity of aberrant patterns of muscle activity. The results obtained in the case study suggest that the proposed technique is suitable to derive clinically-relevant information from EMG data collected during functional evaluations.

Recent machine learning advancements in sensor-based mobility analysis: Deep learning for Parkinson's disease assessment.

The development of wearable sensors has opened the door for long-term assessment of movement disorders. However, there is still a need for developing methods suitable to monitor motor symptoms in and outside the clinic. The purpose of this paper was to investigate deep learning as a method for this monitoring. Deep learning recently broke records in speech and image classification, but it has not been fully investigated as a potential approach to analyze wearable sensor data. We collected data from ten patients with idiopathic Parkinson's disease using inertial measurement units. Several motor tasks were expert-labeled and used for classification. We specifically focused on the detection of bradykinesia. For this, we compared standard machine learning pipelines with deep learning based on convolutional neural networks. Our results showed that deep learning outperformed other state-of-the-art machine learning algorithms by at least 4.6 % in terms of classification rate. We contribute a discussion of the advantages and disadvantages of deep learning for sensor-based movement assessment and conclude that deep learning is a promising method for this field.

On Integration and Validation of a Very Low Complexity ATC UWB System for Muscle Force Transmission.

The thresholding of Surface ElectroMyoGraphic (sEMG) signals, i.e., Average Threshold Crossing (ATC) technique, reduces the amount of data to be processed enabling circuit complexity reduction and low power consumption. This paper investigates the lowest level of complexity reachable by an ATC system through measurements and in-vivo experiments with an embedded prototype for wireless force transmission, based on asynchronous Impulse-Radio Ultra Wide Band (IR-UWB). The prototype is composed by the acquisition unit, a wearable PCB 23 × 34 mm, which includes a full custom IC integrating a UWB transmitter (chip active silicon area 0.016 mm(2), 1 mW power consumption), and the receiver. The system is completely asynchronous, it acquires a differential sEMG signal, generates the ATC events and triggers a 3.3 GHz IR-UWB transmission. ATC robustness relaxes filters constraints: two passive first order filters have been implemented, bandwidth from 10 Hz up to 1 kHz. Energy needed for the single pulse generation is 30 pJ while the whole PCB consumes 5.65 mW. The pulses radiated by the acquisition unit TX are received by a short-range and low complexity threshold-based 130 nm CMOS IR-UWB receiver with an Ultra Low Power (ULP) baseband unit capable of robustly receiving generic quasi-digital pulse sequences. The acquisition unit have been tested with 10 series of in vivo isometric and isotonic contractions, while the transmission channel with over-the-air and cable measurements obtained with a couple of planar monopole antennas and an integrated 0.004 mm(2) transmitter, the same used for the acquisition unit, with realistic channel conditions. The entire system, acquisition unit and receiver, consumes 15.49 mW.