Standing Balance Conditions and Digital Sway Measures for Clinical Trials of Friedreich's Ataxia.

BACKGROUND: Progressive loss of standing balance is a feature of Friedreich's ataxia (FRDA). OBJECTIVES: This study aimed to identify standing balance conditions and digital postural sway measures that best discriminate between FRDA and healthy controls (HC). We assessed test-retest reliability and correlations between sway measures and clinical scores. METHODS: Twenty-eight subjects with FRDA and 20 HC completed six standing conditions: feet apart, feet together, and feet tandem, both with eyes opened (EO) and eyes closed. Sway was measured using a wearable sensor on the lumbar spine for 30 seconds. Test completion rate, test-retest reliability with intraclass correlation coefficients, and areas under the receiver operating characteristic curves (AUCs) for each measure were compared to identify distinguishable FRDA sway characteristics from HC. Pearson correlations were used to evaluate the relationships between discriminative measures and clinical scores. RESULTS: Three of the six standing conditions had completion rates over 70%. Of these three conditions, natural stance and feet together with EO showed the greatest completion rates. All six of the sway measures' mean values were significantly different between FRDA and HC. Four of these six measures discriminated between groups with >0.9 AUC in all three conditions. The Friedreich Ataxia Rating Scale Upright Stability and Total scores correlated with sway measures with P-values <0.05 and r-values (0.63-0.86) and (0.65-0.81), respectively. CONCLUSION: Digital postural sway measures using wearable sensors are discriminative and reliable for assessing standing balance in individuals with FRDA. Natural stance and feet together stance with EO conditions suggest use in clinical trials for FRDA. © 2024 International Parkinson and Movement Disorder Society.

Digital Measures of Postural Sway Quantify Balance Deficits in Spinocerebellar Ataxia.

BACKGROUND: Maintaining balance is crucial for independence and quality of life. Loss of balance is a hallmark of spinocerebellar ataxia (SCA). OBJECTIVE: The aim of this study was to identify which standing balance conditions and digital measures of body sway were most discriminative, reliable, and valid for quantifying balance in SCA. METHODS: Fifty-three people with SCA (13 SCA1, 13 SCA2, 14 SCA3, and 13 SCA6) and Scale for Assessment and Rating of Ataxia (SARA) scores 9.28 ± 4.36 and 31 healthy controls were recruited. Subjects stood in six test conditions (natural stance, feet together and tandem, each with eyes open [EO] and eyes closed [EC]) with an inertial sensor on their lower back for 30 seconds (×2). We compared test completion rate, test-retest reliability, and areas under the receiver operating characteristic curve (AUC) for seven digital sway measures. Pearson's correlations related sway with the SARA and the Patient-Reported Outcome Measure of Ataxia (PROM ataxia). RESULTS: Most individuals with SCA (85%-100%) could stand for 30 seconds with natural stance EO or EC, and with feet together EO. The most discriminative digital sway measures (path length, range, area, and root mean square) from the two most reliable and discriminative conditions (natural stance EC and feet together EO) showed intraclass correlation coefficients from 0.70 to 0.91 and AUCs from 0.83 to 0.93. Correlations of sway with SARA were significant (maximum r = 0.65 and 0.73). Correlations with PROM ataxia were mild to moderate (maximum r = 0.56 and 0.34). CONCLUSION: Inertial sensor measures of extent of postural sway in conditions of natural stance EC and feet together stance EO were discriminative, reliable, and valid for monitoring SCA. © 2024 International Parkinson and Movement Disorder Society.

Assessment of Mobility Trajectories Using Wearable Inertial Sensors During Autologous Hematopoietic Cell Transplant.

OBJECTIVE: This study aimed to characterize mobility patterns using wearable inertial sensors and serial assessment across autologous hematopoietic cell transplant (autoHCT) and investigate the relation between mobility and perceived function in patients with hematologic cancer. DESIGN: Prospective longitudinal study. SETTING: Hospital adult transplant clinic followed by discharge. PARTICIPANTS: 78 patients with hematological cancer receiving autoHCT. MAIN OUTCOME MEASURES: Mobility was measured across 3 clinical phases (pretransplant, pre-engraftment, and post-engraftment) in using inertial sensors worn during prescribed performance tests in the hospital. Perceived function was assessed using validated provider-reported (Eastern Cooperative Oncology Group [ECOG] Performance Status Scale) and patient-reported [European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]) measures. Trajectories of 5 selected mobility characteristics (turn duration, gait speed, stride time variability, double support time, and heel strike angle) across the clinical phases were also evaluated using piecewise linear mixed-effects models. RESULTS: Using Principal Components Analysis, 4 mobility patterns were identified pretransplant: Gait Limitation, Sagittal Sway, Coronal Sway, and Balance Control. Gait Limitation measured pretransplant was significantly inversely associated with perceived function reported by the provider- (ß = -0.11; 95% CI: -0.19, -0.02) and patient- (ß = -4.85; 95% CI: -7.72, -1.99) post-engraftment in age-adjusted linear regression models. Mobility characteristics demonstrated immediate declines early pre-engraftment with stabilization by late pre-engraftment. CONCLUSION: Patients with hematological cancer experiencing gait limitations pretransplant are likely to have worse perceived function post-engraftment. Mobility declines in early phases post-transplant and may not fully recover, indicating an opportunity for timely rehabilitation referrals. Wearable inertial sensors can be used to identify early mobility problems and patients who may be at risk for future functional decline who may be candidates for early physical rehabilitation.

Identifying trajectories and predictors of chemotherapy-induced peripheral neuropathy symptoms, physical functioning, and falls across treatment and recovery in adults treated with neurotoxic chemotherapy: the PATTERN observational study protocol (NCT05790538).

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting side effect of systemic cancer therapy. In many cancer survivors, CIPN persists after treatment ends and is associated with functional impairments, abnormal gait patterns, falls, and diminished quality of life. However, little is known regarding which patients are most likely to develop CIPN symptoms that impair mobility and increase fall risk, when this risk develops, or the optimal timing of early intervention efforts to mitigate the impact of CIPN on functioning and fall risk. This study will address these knowledge gaps by (1) characterizing trajectories of symptoms, functioning, and falls before, during, and after treatment in adults prescribed neurotoxic chemotherapy for cancer; and (2) determining the simplest set of predictors for identifying individuals at risk for CIPN-related functional decline and falls. METHODS: We will enroll 200 participants into a prospective, observational study before initiating chemotherapy and up to 1 year after completing chemotherapy. Eligible participants are aged 40-85 years, diagnosed with stage I-III cancer, and scheduled to receive neurotoxic chemotherapy. We perform objective assessments of vibratory and touch sensation (biothesiometry, tuning fork, monofilament tests), standing and dynamic balance (quiet stance, Timed-Up-and-Go tests), and upper and lower extremity strength (handgrip dynamometry, 5-time repeated chair stand test) in the clinic at baseline, every 4-6 weeks during chemotherapy, and quarterly for 1 year post-chemotherapy. Participants wear devices that passively and continuously measure daily gait quality and physical activity for 1 week after each objective assessment and self-report symptoms (CIPN, insomnia, fatigue, dizziness, pain, cognition, anxiety, and depressive symptoms) and falls via weekly electronic surveys. We will use structural equation modeling, including growth mixture modeling, to examine patterns in trajectories of changes in symptoms, functioning, and falls associated with neurotoxic chemotherapy and then search for distinct risk profiles for CIPN. DISCUSSION: Identifying simple, early predictors of functional decline and fall risk in adults with cancer receiving neurotoxic chemotherapy will help identify individuals who would benefit from early and targeted interventions to prevent CIPN-related falls and disability. TRIAL REGISTRATION: This study was retrospectively registered with ClinicalTrials.gov (NCT05790538) on 3/30/2023.

Quantitative Gait and Balance Outcomes for Ataxia Trials: Consensus Recommendations by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers.

With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials.This narrative review with embedded consensus will describe evidence for the sensitivity of digital gait and balance measures for evaluating ataxia severity and progression, propose a consensus protocol for establishing gait and balance metrics in natural history studies and clinical trials, and discuss relevant issues for their use as performance outcomes.

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.

Balance telerehabilitation and wearable technology for people with Parkinson's disease (TelePD trial).

BACKGROUND: Balance impairments, that lead to falls, are one of the main symptoms of Parkinson's disease (PD). Telerehabilitation is becoming more common for people with PD; however, balance is particularly challenging to assess and treat virtually. The feasibility and efficacy of virtual assessment and virtual treatment of balance in people with PD are unknown. The present study protocol has three aims: I) to determine if a virtual balance and gait assessment (instrumented L-shape mobility test) with wearable sensors can predict a gold-standard, in-person clinical assessment of balance, the Mini Balance Evaluation Systems Test (Mini-BESTest); II) to explore the effects of 12 sessions of balance telerehabilitation and unsupervised home exercises on balance, gait, executive function, and clinical scales; and III) to explore if improvements after balance telerehabilitation transfer to daily-life mobility, as measured by instrumented socks with inertial sensors worn for 7 days. METHODS: The TelePD Trial is a prospective, single-center, parallel-group, single-blind, pilot, randomized, controlled trial. This trial will enroll 80 eligible people with PD. Participants will be randomized at a 1:1 ratio into receiving home-based balance exercises in either: 1) balance telerehabilitation (experimental group, n = 40) or 2) unsupervised exercises (control group, n = 40). Both groups will perform 12 sessions of exercise at home that are 60 min long. The primary outcome will be Mini-BESTest. The secondary outcomes will be upper and lower body gait metrics from a prescribed task (instrumented L-shape mobility test); daily-life mobility measures over 7 days with wearable sensors in socks, instrumented executive function tests, and clinical scales. Baseline testing and 7 days of daily-life mobility measurement will occur before and after the intervention period. CONCLUSION: The TelePD Trial will be the first to explore the usefulness of using wearable sensor-based measures of balance and gait remotely to assess balance, the feasibility and efficacy of balance telerehabilitation in people with PD, and the translation of balance improvements after telerehabilitation to daily-life mobility. These results will help to develop a more effective home-based balance telerehabilitation and virtual assessment that can be used remotely in people with balance impairments. TRIAL REGISTRATION: This trial was prospectively registered on ClinicalTrials.gov (NCT05680597).

Exploring the effects of dopamine on sensorimotor inhibition and mobility in older adults.

Dopaminergic activity decreases in older adults (OAs) with normal aging and is further reduced in Parkinson's disease (PD), affecting cortical motor and sensorimotor pathways. Levodopa is the prevailing therapy to counter dopamine loss in PD, though not all PD motor signs improve with levodopa. The purpose of this preliminary study was to explore the effects of levodopa on sensorimotor inhibition, gait and quiet standing in OAs and to investigate the relationships between sensorimotor inhibition and both gait and standing balance both OFF- and ON-levodopa. Fifteen OA males completed a gait, balance and sensorimotor assessments before and 1 h after they were given a 100 mg dose of levodopa. Short-latency afferent inhibition quantified sensorimotor inhibition. Wearable sensors characterized gait (two-minute walk) and standing balance (1-min stance). No sensorimotor inhibition, gait, or standing balance measures changed from OFF- to ON-levodopa. When OFF-levodopa, worse inhibition significantly related to increased double stance (r = 0.62; p = 0.01), increased jerkiness of sway (r = 0.57; p = 0.03) and sway area (r = 0.58; p = 0.02). While ON-levodopa, worse inhibition related to increased arm swing range of motion (r = 0.63; p = 0.01) and jerkiness of sway (r = 0.53; p = 0.04). The relationship between SAI and arm swing excursion significantly changed from OFF- to ON-levodopa (z = - 3.05; p = 0.002; 95% confidence interval = - 0.95, - 0.21). Sensorimotor inhibition relationships to both gait and balance may be affected by dopamine in OAs. Cortical restructuring due to the loss of dopamine may be responsible for the heterogeneity of levodopa effect in people with PD and OAs.

Mobility Rehab visual feedback system for gait rehabilitation in older adults.

BACKGROUND: Gait and balance impairments are among the main causes of falls in older adults. The feasibility and effectiveness of adding sensor-based feedback to physical therapy (PT) in an outpatient PT setting is unknown. We evaluated the feasibility and effectiveness of PT intervention combined with a therapist-assisted visual feedback system, called Mobility Rehab, (PT + MR) in older adults. METHODS: Twenty-eight older adults with and without neurological diseases were assigned either PT + MR (n = 22) or PT alone (n = 6). Both groups performed 8 sessions (individualized) of 45 min long (30 min for gait training and 15 min for endurance, strength, and balance exercises) in an outpatient clinic. Mobility Rehab uses unobtrusive, inertial sensors on both wrists and feet, and at the sternum level with real-time algorithms to provide real-time feedback on five gait metrics (step duration, stride length, elevation at mid-swing, arm swing range-of-motion [ROM], and trunk coronal ROM), which are displayed on a tablet. The primary outcome was the Activities-specific Balance Confidence scale (ABC). The secondary outcome was gait speed measured with wearable inertial sensors during 2 min of walking. RESULTS: There were no between-group differences at baseline for any variable (P > 0.05). Neither PT + MR nor PT alone showed significant changes on the ABC scores. PT + MR, but not PT alone, showed significant improvements in gait speed and arm swing ROM. The system was evaluated as 'easy to use' by the PT. CONCLUSIONS: Our preliminary results show that PT + MR improves gait speed in older adults with and without neurological diseases in an outpatient clinic. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov , identifier: NCT03869879.

Opal Actigraphy (Activity and Sleep) Measures Compared to ActiGraph: A Validation Study.

Physical activity and sleep monitoring in daily life provide vital information to track health status and physical fitness. The aim of this study was to establish concurrent validity for the new Opal Actigraphy solution in relation to the widely used ActiGraph GT9X for measuring physical activity from accelerometry epic counts (sedentary to vigorous levels) and sleep periods in daily life. Twenty participants (age 56 + 22 years) wore two wearable devices on each wrist for 7 days and nights, recording 3-D accelerations at 30 Hz. Bland-Altman plots and intraclass correlation coefficients (ICCs) assessed validity (agreement) and test-retest reliability between ActiGraph and Opal Actigraphy sleep durations and activity levels, as well as between the two different versions of the ActiGraph. ICCs showed excellent reliability for physical activity measures and moderate-to-excellent reliability for sleep measures between Opal versus Actigraph GT9X and between GT3X versus GT9X. Bland-Altman plots and mean absolute percentage error (MAPE) also show a comparable performance (within 10%) between Opal and ActiGraph and between the two ActiGraph monitors across activity and sleep measures. In conclusion, physical activity and sleep measures using Opal Actigraphy demonstrate performance comparable to that of ActiGraph, supporting concurrent validation. Opal Actigraphy can be used to quantify activity and monitor sleep patterns in research and clinical studies.

Feasibility of a Novel Therapist-Assisted Feedback System for Gait Training in Parkinson's Disease.

We tested the feasibility of one session of treadmill training using a novel physical therapist assisted system (Mobility Rehab) using wearable sensors on the upper and lower limbs of 10 people with Parkinson's disease (PD). Participants performed a 2-min walk overground before and after 15 min of treadmill training with Mobility Rehab, which included an electronic tablet (to visualize gait metrics) and five Opal sensors placed on both the wrists and feet and on the sternum area to measure gait and provide feedback on six gait metrics (foot-strike angle, trunk coronal range-of-motion (ROM), arm swing ROM, double-support duration, gait-cycle duration, and step asymmetry). The physical therapist used Mobility Rehab to select one or two gait metrics (from the six) to focus on during the treadmill training. Foot-strike angle (effect size (ES) = 0.56, 95% Confidence Interval (CI) = 0.14 to 0.97), trunk coronal RoM (ES = 1.39, 95% CI = 0.73 to 2.06), and arm swing RoM (ES = 1.64, 95% CI = 0.71 to 2.58) during overground walking showed significant and moderate-to-large ES following treadmill training with Mobility Rehab. Participants perceived moderate (60%) and excellent (30%) effects of Mobility Rehab on their gait. No adverse events were reported. One session of treadmill training with Mobility Rehab is feasible for people with mild-to-moderate PD.

Fall Prediction Based on Instrumented Measures of Gait and Turning in Daily Life in People with Multiple Sclerosis.

This study investigates the potential of passive monitoring of gait and turning in daily life in people with multiple sclerosis (PwMS) to identify those at future risk of falls. Seven days of passive monitoring of gait and turning were carried out in a pilot study of 26 PwMS in home settings using wearable inertial sensors. The retrospective fall history was collected at the baseline. After gait and turning data collection in daily life, PwMS were followed biweekly for a year and were classified as fallers if they experienced >1 fall. The ability of short-term passive monitoring of gait and turning, as well as retrospective fall history to predict future falls were compared using receiver operator curves and regression analysis. The history of retrospective falls was not identified as a significant predictor of future falls in this cohort (AUC = 0.62, p = 0.32). Among quantitative monitoring measures of gait and turning, the pitch at toe-off was the best predictor of falls (AUC = 0.86, p < 0.01). Fallers had a smaller pitch of their feet at toe-off, reflecting less plantarflexion during the push-off phase of walking, which can impact forward propulsion and swing initiation and can result in poor foot clearance and an increased metabolic cost of walking. In conclusion, our cohort of PwMS showed that objective monitoring of gait and turning in daily life can identify those at future risk of falls, and the pitch at toe-off was the single most influential predictor of future falls. Therefore, interventions aimed at improving the strength of plantarflexion muscles, range of motion, and increased proprioceptive input may benefit PwMS at future fall risk.

Inertial Sensor Algorithm to Estimate Walk Distance.

The "total distance walked" obtained during a standardized walking test is an integral component of physical fitness and health status tracking in a range of consumer and clinical applications. Wearable inertial sensors offer the advantages of providing accurate, objective, and reliable measures of gait while streamlining walk test administration. The aim of this study was to develop an inertial sensor-based algorithm to estimate the total distance walked using older subjects with impaired fasting glucose (Study I), and to test the generalizability of the proposed algorithm in patients with Multiple Sclerosis (Study II). All subjects wore two inertial sensors (Opals by Clario-APDM Wearable Technologies) on their feet. The walking distance algorithm was developed based on 108 older adults in Study I performing a 400 m walk test along a 20 m straight walkway. The validity of the algorithm was tested using a 6-minute walk test (6MWT) in two sub-studies of Study II with different lengths of a walkway, 15 m (Study II-A, n = 24) and 20 m (Study II-B, n = 22), respectively. The start and turn around points were marked with lines on the floor while smaller horizontal lines placed every 1 m served to calculate the manual distance walked (ground truth). The proposed algorithm calculates the forward distance traveled during each step as the change in the horizontal position from each foot-flat period to the subsequent foot-flat period. The total distance walked is then computed as the sum of walk distances for each stride, including turns. The proposed algorithm achieved an average absolute error rate of 1.92% with respect to a fixed 400 m distance for Study I. The same algorithm achieved an absolute error rate of 4.17% and 3.21% with respect to an averaged manual distance for 6MWT in Study II-A and Study II-B, respectively. These results demonstrate the potential of an inertial sensor-based algorithm to estimate a total distance walked with good accuracy with respect to the manual, clinical standard. Further work is needed to test the generalizability of the proposed algorithm with different administrators and populations, as well as larger diverse cohorts.

Cortical thickness as predictor of response to exercise in people with Parkinson's disease.

We previously showed that dual-task cost (DTC) on gait speed in people with Parkinson's disease (PD) improved after 6 weeks of the Agility Boot Camp with Cognitive Challenge (ABC-C) exercise program. Since deficits in dual-task gait speed are associated with freezing of gait and gray matter atrophy, here we performed preplanned secondary analyses to answer two questions: (a) Do people with PD who are freezers present similar improvements compared to nonfreezers in DTC on gait speed with ABC-C? (b) Can cortical thickness at baseline predict responsiveness to the ABC-C? The DTC from 39 freezers and 43 nonfreezers who completed 6 weeks of ABC-C were analyzed. A subset of 51 participants (21 freezers and 30 nonfreezers) with high quality imaging data were used to characterize relationships between baseline cortical thickness and delta (Δ) DTC on gait speed following ABC-C. Freezers showed larger ΔDTC on gait speed than nonfreezers with ABC-C program (p < .05). Cortical thickness in visual and fronto-parietal areas predicted ΔDTC on gait speed in freezers, whereas sensorimotor-lateral thickness predicted ΔDTC on gait speed in nonfreezers (p < .05). When matched for motor severity, visual cortical thickness was a common predictor of response to exercise in all individuals, presenting the largest effect size. In conclusion, freezers improved gait automaticity even more than nonfreezers from cognitively challenging exercise. DTC on gait speed improvement was associated with larger baseline cortical thickness from different brain areas, depending on freezing status, but visual cortex thickness showed the most robust relationship with exercise-induced improvements in DTC.

Gait Variability in Spinocerebellar Ataxia Assessed Using Wearable Inertial Sensors.

BACKGROUND: Quantitative assessment of severity of ataxia-specific gait impairments from wearable technology could provide sensitive performance outcome measures with high face validity to power clinical trials. OBJECTIVES: The aim of this study was to identify a set of gait measures from body-worn inertial sensors that best discriminate between people with prodromal or manifest spinocerebellar ataxia (SCA) and age-matched, healthy control subjects (HC) and determine how these measures relate to disease severity. METHODS: One hundred and sixty-three people with SCA (subtypes 1, 2, 3, and 6), 42 people with prodromal SCA, and 96 HC wore 6 inertial sensors while performing a natural pace, 2-minute walk. Areas under the receiver operating characteristic curves (AUC) were compared for 25 gait measures, including standard deviations as variability, to discriminate between ataxic and normal gait. Pearson's correlation coefficient assessed the relationships between the gait measures and severity of ataxia. RESULTS: Increased gait variability was the most discriminative gait feature of SCA; toe-out angle variability (AUC = 0.936; sensitivity = 0.871; specificity = 0.896) and double-support time variability (AUC = 0.932; sensitivity = 0.834; specificity = 0.865) were the most sensitive and specific measures. These variability measures were also significantly correlated with the scale for the assessment and rating of ataxia (SARA) and disease duration. The same gait measures discriminated gait of people with prodromal SCA from the gait of HC (AUC = 0.610, and 0.670, respectively). CONCLUSIONS: Wearable inertial sensors provide sensitive and specific measures of excessive gait variability in both manifest and prodromal SCAs that are reliable and related to the severity of the disease, suggesting they may be useful as clinical trial performance outcome measures. © 2021 International Parkinson and Movement Disorder Society.

Prodromal Spinocerebellar Ataxia Type 2 Subjects Have Quantifiable Gait and Postural Sway Deficits.

BACKGROUND: The search for valid preclinical biomarkers of cerebellar dysfunction is a key research goal for the upcoming era of early interventional approaches in spinocerebellar ataxias. This study aims to describe novel preclinical biomarkers of subtle gait and postural sway abnormalities in prodromal spinocerebellar ataxia type 2 (pre-SCA2). METHODS: Thirty pre-SCA2 patients and their matched healthy controls underwent quantitative assessments of gait and postural sway using a wearable sensor-based system and semiquantitative evaluation of cerebellar features by SARA (Scale for the Assessment and Rating of Ataxia) score. RESULTS: Quantitative analysis of natural gait showed a significantly larger variability of the swing period, toe-off angle and toe-out angle in pre-SCA2, and larger mean coronal and transverse ranges of motion of the trunk at the lumbar location and of the sagittal range of motion of the trunk at the sternum location compared to controls. During tandem gait, pre-SCA2 subjects showed larger lumbar, trunk, and arm ranges of motion than controls. Postural sway analysis showed excessive body oscillation that was increased in tandem stance. Overall, these abnormalities were detected in pre-SCA2 patients without clinical evidence of abnormalities in SARA. The toe-off angle and swing time variability were significantly correlated with the time to ataxia onset, whereas the toe-off angle and transverse range of motion at trunk position during tandem gait were significantly associated with the SARA score. CONCLUSIONS: This study demonstrates early alteration of gait and postural sway control in prodromal SCA2 using a wearable sensor-based system. This offers new pathophysiological hints into this early disease stage and provides novel potential biomarkers for future clinical trials. © 2020 International Parkinson and Movement Disorder Society.

The Adapted Resistance Training with Instability Randomized Controlled Trial for Gait Automaticity.

BACKGROUND: Deficits in the cerebellar locomotor region (CLR) have been associated with loss of gait automaticity in individuals with freezing of gait in Parkinson's disease (freezers); however, exercise interventions that restore gait automaticity in freezers are lacking. We evaluated the effects of the adapted resistance training with instability ([ARTI] complex exercises) compared with traditional motor rehabilitation (without complex exercises) on gait automaticity and attentional set-shifting. We also verified associations between gait automaticity change and CLR activation change previously published. METHODS: Freezers were randomized either to the experimental group (ARTI, n = 17) or to the active control group (traditional motor rehabilitation, n = 15). Both training groups performed exercises 3 times a week for 12 weeks. Gait automaticity (dual-task and dual-task cost [DTC] on gait speed and stride length), single-task gait speed and stride length, attentional set-shifting (time between Trail Making Test parts B and A), and CLR activation during a functional magnetic resonance imaging protocol of simulated step initiation task were evaluated before and after interventions. RESULTS: Both training groups improved gait parameters in single task (P < 0.05), but ARTI was more effective than traditional motor rehabilitation in improving DTC on gait speed, DTC on stride length, dual-task stride length, and CLR activation (P < 0.05). Changes in CLR activation were associated with changes in DTC on stride length (r = 0.68, P = 0.002) following ARTI. Only ARTI improved attentional set-shifting at posttraining (P < 0.05). CONCLUSIONS: ARTI restores gait automaticity and improves attentional set-shifting in freezers attributed to the usage of exercises with high motor complexity. © 2020 International Parkinson and Movement Disorder Society.

Relating Response Inhibition, Brain Connectivity, and Freezing of Gait in People with Parkinson's Disease.

OBJECTIVE: Freezing of gait (FoG) in Parkinson's disease (PD) has been associated with response inhibition. However, the relationship between response inhibition, neural dysfunction, and PD remains unclear. We assessed response inhibition and microstructural integrity of brain regions involved in response inhibition [right hemisphere inferior frontal cortex (IFC), bilateral pre-supplementary motor areas (preSMA), and subthalamic nuclei (STN)] in PD subjects with and without FoG and elderly controls. METHOD: Twenty-one people with PD and FoG (PD-FoG), 18 without FoG (PD-noFoG), and 19 age-matched controls (HC) completed a Stop-Signal Task (SST) and MRI scan. Probabilistic fiber tractography assessed structural integrity (fractional anisotropy, FA) among IFC, preSMA, and STN regions. RESULTS: Stop-signal performance did not differ between PD and HC, nor between PD-FoG and PD-noFoG. Differences in white matter integrity were observed across groups (.001 < p < .064), but were restricted to PD versus HC groups; no differences in FA were observed between PD-FoG and PD-noFoG (p > .096). Interestingly, worse FoG was associated with higher (better) mean FA in the r-preSMA, (ß = .547, p = .015). Microstructural integrity of the r-IFC, r-preSMA, and r-STN tracts correlated with stop-signal performance in HC (p ≤ .019), but not people with PD. CONCLUSION: These results do not support inefficient response inhibition in PD-FoG. Those with PD exhibited white matter loss in the response inhibition network, but this was not associated with FoG, nor with response inhibition deficits, suggesting FoG-specific neural changes may occur outside the response inhibition network. As shown previously, white matter loss was associated with response inhibition in elderly controls, suggesting PD may disturb this relationship.

Measuring freezing of gait during daily-life: an open-source, wearable sensors approach.

BACKGROUND: Although a growing number of studies focus on the measurement and detection of freezing of gait (FoG) in laboratory settings, only a few studies have attempted to measure FoG during daily life with body-worn sensors. Here, we presented a novel algorithm to detect FoG in a group of people with Parkinson's disease (PD) in the laboratory (Study I) and extended the algorithm in a second cohort of people with PD at home during daily life (Study II). METHODS: In Study I, we described of our novel FoG detection algorithm based on five inertial sensors attached to the feet, shins and lumbar region while walking in 40 participants with PD. We compared the performance of the algorithm with two expert clinical raters who scored the number of FoG episodes from video recordings of walking and turning based on duration of the episodes: very short (< 1 s), short (2-5 s), and long (> 5 s). In Study II, a different cohort of 48 people with PD (with and without FoG) wore 3 wearable sensors on their feet and lumbar region for 7 days. Our primary outcome measures for freezing were the % time spent freezing and its variability. RESULTS: We showed moderate to good agreement in the number of FoG episodes detected in the laboratory (Study I) between clinical raters and the algorithm (if wearable sensors were placed on the feet) for short and long FoG episodes, but not for very short FoG episodes. When extending this methodology to unsupervised home monitoring (Study II), we found that percent time spent freezing and the variability of time spent freezing differentiated between people with and without FoG (p < 0.05), and that short FoG episodes account for 69% of the total FoG episodes. CONCLUSION: Our findings showed that objective measures of freezing in PD using inertial sensors on the feet in the laboratory are matching well with clinical scores. Although results found during daily life are promising, they need to be validated. Objective measures of FoG with wearable technology during community-living would be useful for managing this distressing feature of mobility disability in PD.

Loss of presynaptic inhibition for step initiation in parkinsonian individuals with freezing of gait.

KEY POINTS: Individuals with freezing of gait (FoG) due to Parkinson's disease (PD) have small and long anticipatory postural adjustments (APAs) associated with delayed step initiation. Individuals with FoG ('freezers') may require functional reorganization of spinal mechanisms to perform APAs due to supraspinal dysfunction. As presynaptic inhibition (PSI) is centrally modulated to allow execution of supraspinal motor commands, it may be deficient in freezers during APAs. We show that freezers presented PSI in quiet stance (control task), but they presented loss of PSI (i.e. higher ratio of the conditioned H-reflex relative to the test H-reflex) during APAs before step initiation (functional task), whereas non-freezers and healthy control individuals presented PSI in both the tasks. The loss of PSI in freezers was associated with both small APA amplitudes and FoG severity. We hypothesize that loss of PSI during APAs for step initiation in freezers may be due to FoG. ABSTRACT: Freezing of gait (FoG) in Parkinson's disease involves deficient anticipatory postural adjustments (APAs), resulting in a cessation of step initiation due to supraspinal dysfunction. Individuals with FoG ('freezers') may require functional reorganization of spinal mechanisms to perform APAs. As presynaptic inhibition (PSI) is centrally modulated to allow execution of supraspinal motor commands, here we hypothesized a loss of PSI in freezers during APA for step initiation, which would be associated with FoG severity. Seventy individuals [27 freezers, 22 non-freezers, and 21 age-matched healthy controls (HC)] performed a 'GO'-commanded step initiation task on a force platform under three conditions: (1) without electrical stimulation, (2) test Hoffman reflex (H-reflex) and (3) conditioned H-reflex. They also performed a control task (quiet stance). In the step initiation task, the H-reflexes were evoked on the soleus muscle when the amplitude of the APA exceeded 10-20% of the mean baseline mediolateral force. PSI was quantified by the ratio of the conditioned H-reflex relative to the test H-reflex in both the tasks. Objective assessment of FoG severity (FoG-ratio) was performed. Freezers presented lower PSI levels during quiet stance than non-freezers and HC (P < 0.05). During step initiation, freezers presented loss of PSI and lower APA amplitudes than non-freezers and HC (P < 0.05). Significant correlations were only found for freezers between loss of PSI and FoG-ratio (r = 0.59, P = 0.0005) and loss of PSI and APA amplitude (r = -0.35, P < 0.036). Our findings suggest that loss of PSI for step initiation in freezers may be due to FoG.