Decomposition of Reaching Movements Enables Detection and Measurement of Ataxia

Technologies that enable frequent, objective, and precise measurement of ataxia severity would benefit clinical trials by lowering participation barriers and improving the ability to measure disease state and change. We hypothesized that analyzing characteristics of sub-second movement profiles obtained during a reaching task would be useful for objectively quantifying motor characteristics of ataxia. Participants with ataxia (N=88), participants with parkinsonism (N=44), and healthy controls (N=34) performed a computer tablet version of the finger-to-nose test while wearing inertial sensors on their wrists. Data features designed to capture signs of ataxia were extracted from participants’ decomposed wrist velocity time-series. A machine learning regression model was trained to estimate overall ataxia severity, as measured by the Brief Ataxia Rating Scale (BARS). Classification models were trained to distinguish between ataxia participants and controls and between ataxia and parkinsonism phenotypes. Movement decomposition revealed expected and novel characteristics of the ataxia phenotype. The distance, speed, duration, morphology, and temporal relationships of decomposed movements exhibited strong relationships with disease severity. The regression model estimated BARS with a root mean square error of 3.6 points, r2 = 0.69, and moderate-to-excellent reliability. Classification models distinguished between ataxia participants and controls and ataxia and parkinsonism phenotypes with areas under the receiver-operating curve of 0.96 and 0.89, respectively. Movement decomposition captures core features of ataxia and may be useful for objective, precise, and frequent assessment of ataxia in home and clinic environments

Quantitative oculomotor assessment in hereditary ataxia: systematic review and consensus by the ataxia global initiative working group on digital-motor biomarkers

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias

Assessing Cerebellar Disorders with Wearable Inertial Sensor Data Using Time-Frequency and Autoregressive Hidden Markov Model Approaches

Wearable sensor data is relatively easily collected and provides direct measurements of movement that can be used to develop useful behavioral biomarkers. Sensitive and specific behavioral biomarkers for neurodegenerative diseases are critical to supporting early detection, drug development efforts, and targeted treatments. In this paper, we use autoregressive hidden Markov models and a time-frequency approach to create meaningful quantitative descriptions of behavioral characteristics of cerebellar ataxias from wearable inertial sensor data gathered during movement. We create a flexible and descriptive set of features derived from accelerometer and gyroscope data collected from wearable sensors worn while participants perform clinical assessment tasks, and use these data to estimate disease status and severity. A short period of data collection (<5 min) yields enough information to effectively separate patients with ataxia from healthy controls with very high accuracy, to separate ataxia from other neurodegenerative diseases such as Parkinson’s disease, and to provide estimates of disease severity

At-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis causes degeneration of motor neurons, resulting in progressive muscle weakness and impairment in motor function. Promising drug development efforts have accelerated in amyotrophic lateral sclerosis, but are constrained by a lack of objective, sensitive, and accessible outcome measures. Here we investigate the use of wearable sensors, worn on four limbs at home during natural behavior, to quantify motor function and disease progression in 376 individuals with amyotrophic lateral sclerosis. We use an analysis approach that automatically detects and characterizes submovements from passively collected accelerometer data and produces a machine-learned severity score for each limb that is independent of clinical ratings. We show that this approach produces scores that progress faster than the gold standard Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (−0.86 ± 0.70 SD/year versus −0.73 ± 0.74 SD/year), resulting in smaller clinical trial sample size estimates (N = 76 versus N = 121). This method offers an ecologically valid and scalable measure for potential use in amyotrophic lateral sclerosis trials and clinical care

Behavioral Correlates of Hippocampal Neural Sequences

Fund. The views and conclusions contained in this document are those of the author and should not be interpreted as representing the official policies, either expressed or implied, of any sponsoring institution, the U.S. government or any other entity. Sequences of neural activity representing paths in an environment are expressed in the rodent hippocampus at three distinct time scales, with different hypothesized roles in hippocampal function. As an animal moves through an environment and passes through a series of place fields, place cells activate and deactivate in sequence, at the time scale of the animal’s movement (i.e., the behavioral time scale). Moreover, at each moment in time, as the animal’s location in the environment overlaps with the firing fields of many place cells, the active place cells fire in sequence during each cycle of the 4-12 Hz theta oscillation observed in the hippocampal local field potentials (i.e., the theta time scale), such that the neural activity, in general, represents a short path that begins slightly behind the animal and ends slightly ahead of the animal. These sequences have been hypothesized to play a role in the encoding and recall of episodes of behavior

Objective Assessment of Upper-Extremity Motor Functions in Spinocerebellar Ataxia Using Wearable Sensors

The study presents a novel approach to objectively assessing the upper-extremity motor symptoms in spinocerebellar ataxia (SCA) using data collected via a wearable sensor worn on the patient&rsquo;s wrist during upper-extremity tasks associated with the Assessment and Rating of Ataxia (SARA). First, we developed an algorithm for detecting/extracting the cycles of the finger-to-nose test (FNT). We extracted multiple features from the detected cycles and identified features and parameters correlated with the SARA scores. Additionally, we developed models to predict the severity of symptoms based on the FNT. The proposed technique was validated on a dataset comprising the seventeen (n = 17) participants&rsquo; assessments. The cycle detection technique showed an accuracy of 97.6% in a Bland&ndash;Altman analysis and a 94% accuracy (F1-score of 0.93) in predicting the severity of the FNT. Furthermore, the dependency of the upper-extremity tests was investigated through statistical analysis, and the results confirm dependency and potential redundancies in the upper-extremity SARA assessments. Our findings pave the way to enhance the utility of objective measures of SCA assessments. The proposed wearable-based platform has the potential to eliminate subjectivity and inter-rater variabilities in assessing ataxia

Using Smartphone Sensors for Ataxia Trials: Consensus Guidance by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers

Smartphone sensors are used increasingly in the assessment of ataxias. To date, there is no specific consensus guidance regarding a priority set of smartphone sensor measurements, or standard assessment criteria that are appropriate for clinical trials. As part of the Ataxia Global Initiative Digital-Motor Biomarkers Working Group (AGI WG4), aimed at evaluating key ataxia clinical domains (gait/posture, upper limb, speech and oculomotor assessments), we provide consensus guidance for use of internal smartphone sensors to assess key domains. Guidance was developed by means of a literature review and a two stage Delphi study conducted by an Expert panel, which surveyed members of AGI WG4, representing clinical, research, industry and patient-led experts, and consensus meetings by the Expert panel to agree on standard criteria and map current literature to these criteria. Seven publications were identified that investigated ataxias using internal smartphone sensors. The Delphi 1 survey ascertained current practice, and systems in use or under development. Wide variations in smartphones sensor use for assessing ataxia were identified. The Delphi 2 survey identified seven measures that were strongly endorsed as priorities in assessing 3/4 domains, namely gait/posture, upper limb, and speech performance. The Expert panel recommended 15 standard criteria to be fulfilled in studies. Evaluation of current literature revealed that none of the studies met all criteria, with most being early-phase validation studies. Our guidance highlights the importance of consensus, identifies priority measures and standard criteria, and will encourage further research into the use of internal smartphone sensors to measure ataxia digital-motor biomarkers