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Parkinson's disease (PD) is a neurodegenerative disorder causing postural control impairments. Postural control involves multiple domains, such as control of postural sway in stance, automatic postural responses (APRs) and anticipatory postural adjustments (APAs). We hypothesize that impairments in each postural domain is associated with resting-state functional connectivity (rsFC), accounted by predictive modeling and that cortical and cerebellar networks would predict postural control in people with PD (PwPD).To determine whether rsFC can predict three domains of postural control independently in PwPD and older adults (OA) based on predictive accuracy of models.The cohort consisted of 65 PwPD (67.7 +8.1 age) tested in their OFF-state and 42 OA (69.7 +8.2 age). Six body-worn, inertial sensors measured postural sway area while standing on foam, step length of APRs to a backward push-and-release perturbation, and magnitude of lateral APAs prior to voluntary gait initiation. Resting state-fMRI data was reported on 384 regions of interest that were grouped into 13 functional brain networks. Associations between rsFC and postural metrics were characterized using predictive modeling, with an independent training (n = 67) and validation (n = 40) dataset. Models were trained in the training sample and performance of the best model was validated in the independent test dataset.rsFC of different brain networks predicted each domain of postural control in PD: Frontoparietal and Ventral Attention rsFC for APAs; Cerebellar-Subcortical and Visual rsFC and Auditory and Cerebellar-Subcortical rsFC for APRs; Ventral Attention and Ventral Multimodal rsFC for postural sway. In OA, CinguloOpercular and Somatomotor rsFC predicted APAs.Our findings suggest that cortical networks predict postural control in PD and there is little overlap in brain network connectivities that predict different domains of postural control, given the rsFC methodology used. PwPD use different cortical networks for APAs compared to OA.

Background: Instrumented measures of balance and gait measure more specific balance and gait impairments than clinical rating scales. No prior studies have used objective balance/gait measures to examine associations with ventricular and brain volumes in people with Parkinson’s disease (PD). Objective: To test the hypothesis that larger ventricular and smaller cortical and subcortical volumes are associated with impaired balance and gait in people with PD. Methods: Regional volumes from structural brain images were included from 96 PD and 50 control subjects. Wearable inertial sensors quantified gait, anticipatory postural adjustments prior to step initiation (APAs), postural responses to a manual push, and standing postural sway on a foam surface. Multiple linear regression models assessed the relationship between brain volumes and balance/gait and their interactions in PD and controls, controlling for sex, age and corrected for multiple comparisons. Results: Smaller brainstem and subcortical gray matter volumes were associated with larger sway area in people with PD, but not healthy controls. In contrast, larger ventricle volume was associated with smaller APAs in healthy controls, but not in people with PD. A sub-analysis in PD showed significant interactions between freezers and non-freezers, in several subcortical areas with stride time variability, gait speed and step initiation. Conclusion: Our models indicate that smaller subcortical and brainstem volumes may be indicators of standing balance dysfunction in people with PD whereas enlarged ventricles may be related to step initiation difficulties in healthy aging. Also, multiple subcortical region atrophy may be associated with freezing of gait in PD.

ispartof: MOVEMENT DISORDERS vol:37 issue:2 pages:264-267 ispartof: location:United States status: published

Background: There is a lack of recommendations for selecting the most appropriate gait measures of Parkinson’s disease (PD)-specific dual-task costs to use in clinical practice and research. Objective: We aimed to identify measures of dual-task costs of gait and turning that best discriminate performance in people with PD from healthy individuals. We also investigated the relationship between the most discriminative measures of dual-task costs of gait and turning with disease severity and disease duration. Methods: People with mild-to-moderate PD (n = 144) and age-matched healthy individuals (n = 79) wore 8 inertial sensors while walking under single and dual-task (reciting every other letter of the alphabet) conditions. Outcome measures included 26 objective measures within four gait domains (upper/lower body, turning and variability). The area under the curve (AUC) from the receiver-operator characteristic plot was calculated to compare discriminative ability of dual-task costs on gait across outcome measures. Results: PD-specific, dual-task interference was identified for arm range of motion, foot strike angle, turn velocity and turn duration. Arm range of motion (AUC = 0.73) and foot strike angle (AUC = 0.68) had the largest AUCs across dual-task costs measures and they were associated with disease severity and/or disease duration. In contrast, the most commonly used dual-task gait measure, gait speed, showed an AUC of only 0.54. Conclusion: Findings suggest that people with PD rely more than healthy individuals on executive-attentional resources to control arm swing, foot strike, and turning, but not gait speed. The dual-task costs of arm range of motion best discriminated people with PD from healthy individuals.

We previously showed that both open-loop (beat of a metronome) and closed-loop (phase-dependent tactile feedback) cueing may be similarly effective in reducing Freezing of Gait (FoG), assessed with a quantitative FoG Index, while turning in place in the laboratory in a group of people with Parkinson's disease (PD). Despite the similar changes on the FoG Index, it is not known whether both cueing responses require attentional control, which would explain FoG Index improvement. The mechanisms underlying cueing responses are poorly understood. Here, we tested the hypothesis that the salience network would predict responsiveness (i.e., FoG Index improvement) to open-loop and closed-loop cueing in people with and without FoG of PD, as salience network contributes to tasks requiring attention to external stimuli in healthy adults. Thirteen people with PD with high-quality imaging data were analyzed to characterize relationships between resting-state MRI functional connectivity and responses to cues. The interaction of the salience network and retrosplenial-temporal networks was the best predictor of responsiveness to open-loop cueing, presenting the largest effect size (d = 1.16). The interaction between the salience network and subcortical as well as cingulo-parietal and subcortical networks were the strongest predictors of responsiveness to closed-loop cueing, presenting the largest effect sizes (d = 1.06 and d = 0.84, respectively). Salience network activity was a common predictor of responsiveness to both cueing, which suggests that auditory and proprioceptive stimuli during turning may require some level of cognitive and insular activity, anchored within the salience network, which explain FoG Index improvements in people with PD.

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

Author(s): Nutt, John G; Curtze, Carolin; Hiller, Amie; Anderson, Shannon; Larson, Paul S; Van Laar, Amber D; Richardson, R Mark; Thompson, Marin E; Sedkov, Alexander; Leinonen, Mika; Ravina, Bernard; Bankiewicz, Krystof S; Christine, Chadwick W | Abstract: BackgroundAs Parkinson's disease progresses, levodopa treatment loses efficacy, partly through the loss of the endogenous dopamine-synthesizing enzyme L-amino acid decarboxylase (AADC). In the phase I PD-1101 study, putaminal administration of VY-AADC01, an investigational adeno-associated virus serotype-2 vector for delivery of the AADC gene in patients with advanced Parkinson's disease, was well tolerated, improved motor function, and reduced antiparkinsonian medication requirements.ObjectivesThis substudy aimed to determine whether the timing and magnitude of motor response to intravenous levodopa changed in PD-1101 patients after VY-AADC01 administration.MethodsParticipants received 2-hour threshold (0.6 mg/kg/h) and suprathreshold (1.2 mg/kg/h) levodopa infusions on each of 2 days, both before and approximately 6 months after VY-AADC01. Infusion order was randomized and double blinded. Unified Parkinson's Disease Rating Scale motor scores, finger-tapping speeds, and dyskinesia rating scores were assessed every 30 minutes for 1 hour before and ≥3 hours after start of levodopa infusion.ResultsOf 15 PD-1101 patients, 13 participated in the substudy. Unified Parkinson's Disease Rating Scale motor score area under the curve responses to threshold and suprathreshold levodopa infusions increased by 168% and 67%, respectively, after VY-AADC01; finger-tapping speeds improved by 162% and 113%, and dyskinesia scores increased by 208% and 72%, respectively, after VY-AADC01. Adverse events (mild/moderate severity) were reported in 5 participants during levodopa infusions pre-VY-AADC01 and 2 participants post-VY-AADC01 administration.ConclusionsVY-AADC01 improved motor responses to intravenous levodopa given under controlled conditions. These data and findings from the parent study support further clinical development of AADC gene therapy for people with Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Clinical trials need to specify which specific gait characteristics to monitor as digital mobility outcomes for each neurological disorder. This study aimed to identify a set of measures from daily-life monitoring that best discriminate mobility between people with Multiple Sclerosis (MS) and age-matched healthy control subjects (MS-Ctl), and between people with Parkinson’s Disease (PD) and age-matched healthy control subjects (PD-Ctl). Further, we investigated how these discriminative measures relate to disease severity of MS or PD. We recruited 13 people with MS, 21 MS-Ctl, 29 people with idiopathic PD, and 20 PD-Ctl. Subjects wore 3 inertial sensors on their feet and the lumbar back for a week. The Area Under Curves (AUC) from receiver operator characteristic (ROC) plots was calculated for each measure to determine the objective measures that best separated the MS and PD groups from their respective control cohorts. Adherence wearing the sensors was similar among groups for 58–66 hours of recording (p=0.14). Quantity of mobility (activity measures, such as median number of strides per gait bout, AUC = 0.93) best discriminated mobility impairments in MS from MS-Ctl. In contrast, quality of mobility (such as turn angle, AUC = 0.90) best discriminated mobility impairments in PD from PD-Ctl. Mobility measures with AUC >.80 were correlated with MS and PD clinical scores of disease severity. Thus, digital outcome measures characterizing mobility impairments differ for MS versus PD during daily life. Hence, digital outcome measures of mobility for clinical trials and clinical practice need to be specific to each neurological disorder.

Introduction Degeneration of cholinergic systems may contribute to impairments of balance and gait in Parkinson's disease (PD) and phase 2 clinical trials have suggested that centrally acting cholinesterase inhibitors reduce falls. Here, we examined the effects of augmenting cholinergic neurotransmission on static and dynamic balance, indices of fall risk. Methods A single-site, randomized, double-blind, crossover trial examined the effect of donepezil in patients with PD. Forty-nine participants with idiopathic PD were randomized and 45 completed the trial. Each treatment period was 6 weeks with a 6-week washout between treatments. Donepezil in 2.5 mg capsules, or identical appearing placebo capsules, was increased from two per day (5 mg) to four capsules (10 mg) after 3 weeks. The primary outcome measures were the range of the medio-lateral sway when standing (static balance) and the variability of the stride duration when walking (dynamic balance). A linear mixed model was used to investigate whether the change in outcomes between weeks 0 and 6 differed between phases. Results There were no significant differences in treatment effects between placebo and donepezil for medio-lateral sway range during quiet standing (p = 0.28), nor in gait variability (p = 0.31). None of the secondary outcome measures or exploratory analyses were significant although one secondary measure of static balance was increased by donepezil. Conclusions Contrary to our hypothesis, cholinergic augmentation with donepezil at 10 mg/day for 6 weeks did not affect measures of static or dynamic balance in people with PD. These results are compared with other phase 2 trials of cholinesterase inhibitors and considerations for future trials are discussed.

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Background: One difficulty in turning algorithm design for inertial sensors is detecting two discrete turns in the same direction, close in time. A second difficulty is under-estimation of turn angle due to short-duration hesitations by people with neurological disorders. We aimed to validate and determine the generalizability of a: I. Discrete Turn Algorithm for variable and sequential turns close in time and II: Merged Turn Algorithm for a single turn angle in the presence of hesitations. Methods: We validated the Discrete Turn Algorithm with motion capture in healthy controls (HC, n = 10) performing a spectrum of turn angles. Subsequently, the generalizability of the Discrete Turn Algorithm and associated, Merged Turn Algorithm were tested in people with Parkinson's disease (PD, n = 124), spinocerebellar ataxia (SCA, n = 51), and HC ( n = 125). Results: The Discrete Turn Algorithm shows improved agreement with optical motion capture and with known turn angles, compared to our previous algorithm by El-Gohary et al. The Merged Turn algorithm that merges consecutive turns in the same direction with short hesitations resulted in turn angle estimates closer to a fixed 180-degree turn angle in the PD, SCA, and HC subjects compared to our previous turn algorithm. Additional metrics were proposed to capture turn hesitations in PD and SCA. Conclusion: The Discrete Turn Algorithm may be particularly useful to characterize turns when the turn angle is unknown, i.e., during free-living conditions. The Merged Turn algorithm is recommended for clinical tasks in which the single-turn angle is known, especially for patients who hesitate while turning.

Mobility deficits, including gait disturbance, balance impairments and falls, are common features of Parkinson's disease (PD) that negatively impact quality of life. Mobility deficits respond poorly to dopaminergic medications, indicating a role for additional neurotransmitters. Due to the critical role of cortical input to gait and balance, acetylcholine—an essential neurotransmitter system for attention—has become an area of interest for mobility. This review aimed to identify the role of cholinergic function on gait, balance, and falls in PD using three techniques; pharmacological, imaging, and electrophysiological. Studies supported the role of the cholinergic system for mobility in PD, with the most promising evidence indicating a role in falls. Imaging studies demonstrated involvement of anterior cholinergic (basal forebrain) systems in gait, and posterior (brainstem) systems in balance. However, this review identified a small number of studies which used varying protocols, making comparisons difficult. Further studies are warranted, measuring comprehensive gait and balance characteristics as well as gold standard falls detection to further quantify the relationship between ACh and mobility in PD.

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 ( 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 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.

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, (β = .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.

Background and purpose Recent findings suggest that a gait assessment at a discrete moment in a clinic or laboratory setting may not reflect functional, everyday mobility. As a step towards better understanding gait during daily life in neurological populations, we compared gait measures that best discriminated people with multiple sclerosis (MS) and people with Parkinson’s Disease (PD) from their respective, age-matched, healthy control subjects (MS-Ctl, PD-Ctl) in laboratory tests versus a week of daily life monitoring. Methods We recruited 15 people with MS (age mean ± SD: 49 ± 10 years), 16 MS-Ctl (45 ± 11 years), 16 people with idiopathic PD (71 ± 5 years), and 15 PD-Ctl (69 ± 7 years). Subjects wore 3 inertial sensors (one each foot and lower back) in the laboratory followed by 7 days during daily life. Mann–Whitney U test and area under the curve (AUC) compared differences between PD and PD-Ctl, and between MS and MS-Ctl in the laboratory and in daily life. Results Participants wore sensors for 60–68 h in daily life. Measures that best discriminated gait characteristics in people with MS and PD from their respective control groups were different between the laboratory gait test and a week of daily life. Specifically, the toe-off angle best discriminated MS versus MS-Ctl in the laboratory (AUC [95% CI] = 0.80 [0.63–0.96]) whereas gait speed in daily life (AUC = 0.84 [0.69–1.00]). In contrast, the lumbar coronal range of motion best discriminated PD versus PD-Ctl in the laboratory (AUC = 0.78 [0.59–0.96]) whereas foot-strike angle in daily life (AUC = 0.84 [0.70–0.98]). AUCs were larger in daily life compared to the laboratory. Conclusions Larger AUC for daily life gait measures compared to the laboratory gait measures suggest that daily life monitoring may be more sensitive to impairments from neurological disease, but each neurological disease may require different gait outcome measures.

Few exercise interventions practice both gait and balance tasks with cognitive tasks to improve functional mobility in people with PD. We aimed to investigate whether the Agility Boot Camp with Cognitive Challenge (ABC-C), that simultaneously targets both mobility and cognitive function, improves dynamic balance and dual-task gait in individuals with Parkinson’s disease (PD). We used a cross-over, single-blind, randomized controlled trial to determine efficacy of the exercise intervention. Eighty-six people with idiopathic PD were randomized into either an exercise (ABC-C)-first or an active, placebo, education-first intervention and then crossed over to the other intervention. Both interventions were carried out in small groups led by a certified exercise trainer (90-min sessions, 3 times a week, for 6 weeks). Outcome measures were assessed Off levodopa at baseline and after the first and second interventions. A linear mixed-effects model tested the treatment effects on the Mini-BESTest for balance, dual-task cost on gait speed, SCOPA-COG, the UPDRS Parts II and III and the PDQ-39. Although no significant treatment effects were observed for the Mini-BESTest, SCOPA-COG or MDS-UPDRS Part III, the ABC-C intervention significantly improved the following outcomes: anticipatory postural adjustment sub-score of the Mini-BESTest (p = 0.004), dual-task cost on gait speed (p = 0.001), MDS-UPDRS Part II score (p = 0.01), PIGD sub-score of MDS-UPDRS Part III (p = 0.02), and the activities of daily living domain of the PDQ-39 (p = 0.003). Participants with more severe motor impairment or more severe cognitive dysfunction improved their total Mini-BESTest scores after exercise. The ABC-C exercise intervention can improve specific balance deficits, cognitive-gait interference, and perceived functional independence and quality of life, especially in participants with more severe PD, but a longer period of intervention may be required to improve global cognitive and motor function.

Degradation of striatal dopamine in Parkinson's disease (PD) may initially be supplemented by increased cognitive control mediated by cholinergic mechanisms. Shift to cognitive control of walking can be quantified by prefrontal cortex activation. Levodopa improves certain aspects of gait and worsens others, and cholinergic augmentation influence on gait and prefrontal cortex activity remains unclear. This study examined dopaminergic and cholinergic influence on gait and prefrontal cortex activity while walking in PD. A single-site, randomized, double-blind crossover trial examined effects of levodopa and donepezil in PD. Twenty PD participants were randomized, and 19 completed the trial. Participants were randomized to either levodopa + donepezil (5 mg) or levodopa + placebo treatments, with 2 weeks with treatment and a 2-week washout. The primary outcome was change in prefrontal cortex activity while walking, and secondary outcomes were change in gait and dual-task performance and attention. Levodopa decreased prefrontal cortex activity compared with off medication (effect size, -0.51), whereas the addition of donepezil reversed this decrease. Gait speed and stride length under single- and dual-task conditions improved with combined donepezil and levodopa compared with off medication (effect size, 1 for gait speed and 0.75 for stride length). Dual-task reaction time was quicker with levodopa compared with off medication (effect size, -0.87), and accuracy improved with combined donepezil and levodopa (effect size, 0.47). Cholinergic therapy, specifically donepezil 5 mg/day for 2 weeks, can alter prefrontal cortex activity when walking and improve secondary cognitive task accuracy and gait in PD. Further studies will investigate whether higher prefrontal cortex activity while walking is associated with gait changes. © 2020 International Parkinson and Movement Disorder Society.

Introduction Cholinergic dysfunction contributes to mobility deficits in Parkinson's disease (PD). People with PD rely on limited prefrontal executive-attentional resources for the control of locomotion, including turning. Cortical and behavioral responses to cholinergic augmentation during turning remains unclear. We examined prefrontal cortex (PFC) activity while turning-in-place and spatiotemporal measures of turns in response to usual dopaminergic medication and adjunct cholinergic augmentation. Methods This study consisted of a single-site, randomized, double-blind crossover trial. Twenty PD participants were assessed in the levodopa-off state and then randomized to either levodopa + donepezil (5 mg) or levodopa + placebo treatments for two weeks followed by a 2-week washout before crossover. The primary outcome was change from off state in PFC activity while turning-in-place (assessed with functional near-infrared spectroscopy). Secondary outcomes were changes in spatiotemporal turning measures (assessed with body-worn inertial measurement units) and accuracy in the secondary task. Results Nineteen participants completed the trial. While levodopa + placebo had no effect on PFC activity when turning-in-place with a dual-task, levodopa + donepezil led to a large reduction in PFC activity (effect size, −0.82). Spatiotemporal measures of turning improved with both treatments, with slightly greater effect sizes observed for levodopa + donepezil. Additionally, the accuracy in the concurrent cognitive task improved only with levodopa + donepezil (effect size, 0.63). Conclusion The addition of cholinergic therapy with donepezil (5 mg/day for 2 weeks) to standard dopaminergic therapy reduced the burden on prefrontal executive-attentional resources while turning with a dual-task and improved secondary task accuracy and turning.

Freezing of gait (FoG) is a brief, episodic absence or marked reduction of forward progression of the feet, despite the intention to walk, that is common in people with Parkinson’s disease (PD). We hypothesized that not only motor, but higher level cognitive and attention areas may be impaired in freezers. In this study, we aimed to characterize differences in cortical and subcortical functional connectivity specific to FoG. We examined resting state neuroimaging and objective measures of FoG severity and gait from 103 individuals (28 PD + FoG, 36 PD − FoG and 39 healthy controls). Inertial sensors were used to quantify freezing severity and gait. Groups with and without FoG were matched on age, disease severity, cognitive status, and levodopa medication. MRI data was processed using surface-based registration. High-quality imaging data were used to characterize differences in connectivity specific to FoG using a pre-defined set of Regions of Interest (ROIs) and validated using whole-brain connectivity analysis. Associations between functional connectivity and objective measures of FoG were determined via predictive modeling using hold-out cross validation. We found that connectivity between the left globus pallidus (GP) and left somatosensory cortex and between two brain areas in the default and insular/vestibular networks exhibited significant differences specific to FoG and were also strong and significant predictors of FoG severity. Our findings suggest that the interplay among motor, default and vestibular areas of the left cortex are critical in the pathology of FoG.

Background: Balance deficits in people with Parkinson's disease (PD) are often not helped by pharmacological or surgical treatment. Although balance exercise intervention has been shown to improve clinical measures of balance, the efficacy of exercise on different, objective balance domains is still unknown.Objective: To compare the sensitivity to change in objective and clinical measures of several different domains of balance and gait following an Agility Boot Camp with Cognitive Challenges (ABC-C) intervention.Methods: In this cross-over, randomized design, 86 individuals with PD participated in 6-week (3×/week) ABC-C exercise classes and 6-week education classes, consisting of 3–6 individuals. Blinded examiners tested people in their practical off state. Objective outcome measures from wearable sensors quantified four domains of balance: sway in standing balance, anticipatory postural adjustments (APAs) during step initiation, postural responses to the push-and-release test, and a 2-min natural speed walk with and without a cognitive task. Clinical outcome measures included the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, the Mini Balance Evaluation Systems Test (Mini-BESTest), the Activities of Balance Confidence (ABC), and the Parkinson's Disease Questionnaire (PDQ-39). The standardized response means (SRM) of the differences between before and after each intervention compared responsiveness of outcomes to intervention. A linear mixed model compared effects of exercise with the active control—education intervention.Results: The most responsive outcome measures to exercise intervention with an SRM > 0.5 were objective measures of gait and APAs, specifically arm range of motion, gait speed during a dual-task walk, trunk coronal range of motion, foot strike angle, and first-step length at step initiation. The most responsive clinical outcome measure was the patient-reported PDQ-39 activities daily living subscore, but all clinical measures had SRMs

Although the use of wearable technology to characterize gait disorders in daily life is increasing, there is no consensus on which specific gait bout length should be used to characterize gait. Clinical trialists using daily life gait quality as study outcomes need to understand how gait bout length affects the sensitivity and specificity of measures to discriminate pathological gait as well as the reliability of gait measures across gait bout lengths. We investigated whether Parkinson&rsquo, s disease (PD) affects how gait characteristics change as bout length changes, and how gait bout length affects the reliability and discriminative ability of gait measures to identify gait impairments in people with PD compared to neurotypical Old Adults (OA). We recruited 29 people with PD and 20 neurotypical OA of similar age for this study. Subjects wore 3 inertial sensors, one on each foot and one over the lumbar spine all day, for 7 days. To investigate which gait bout lengths should be included to extract gait measures, we determined the range of gait bout lengths available across all subjects. To investigate if the effect of bout length on each gait measure is similar or not between subjects with PD and OA, we used a growth curve analysis. For reliability and discriminative ability of each gait measure as a function of gait bout length, we used the intraclass correlation coefficient (ICC) and area under the curve (AUC), respectively. Ninety percent of subjects walked with a bout length of less than 53 strides during the week, and the majority (&gt, 50%) of gait bouts consisted of less than 12 strides. Although bout length affected all gait measures, the effects depended on the specific measure and sometimes differed for PD versus OA. Specifically, people with PD did not increase/decrease cadence and swing duration with bout length in the same way as OA. ICC and AUC characteristics tended to be larger for shorter than longer gait bouts. Our findings suggest that PD interferes with the scaling of cadence and swing duration with gait bout length. Whereas control subjects gradually increased cadence and decreased swing duration as bout length increased, participants with PD started with higher than normal cadence and shorter than normal stride duration for the smallest bouts, and cadence and stride duration changed little as bout length increased, so differences between PD and OA disappeared for the longer bout lengths. Gait measures extracted from shorter bouts are more common, more reliable, and more discriminative, suggesting that shorter gait bouts should be used to extract potential digital biomarkers for people with PD.

Freezing of gait (FOG) is common in people with Parkinson’s disease (PD) which is extremely debilitating. One hypothesis for the cause of FOG episodes is impaired cognitive control, however, this is still in debate in the literature. We aimed to assess a comprehensive range of cognitive tests in older adults and people with Parkinson’s with and without FOG and associate FOG severity with cognitive performance. A total of 227 participants took part in the study which included 80 healthy older adults, 81 people with PD who did not have FOG and 66 people with PD and FOG. A comprehensive battery of neuropsychological assessments tested cognitive domains of global cognition, executive function/attention, working memory, and visuospatial function. The severity of FOG was assessed using the new FOG questionnaire and an objective FOG severity score. Cognitive performance was compared between groups using an ANCOVA adjusting for age, gender, years of education and disease severity. Correlations between cognitive performance and FOG severity were analyzed using partial correlations. Cognitive differences were observed between older adults and PD for domains of global cognition, executive function/attention, and working memory. Between those with and without FOG, there were differences for global cognition and executive function/attention, but these differences disappeared when adjusting for covariates. There were no associations between FOG severity and cognitive performance. This study identified no significant difference in cognition between those with and without FOG when adjusting for covariates, particularly disease severity. This may demonstrate that complex rehabilitation programs may be undertaken in those with FOG.

Introduction. It is well documented that freezing of gait (FoG) episodes occur in situations that are mentally challenging, such as dual tasks, consistent with less automatic control of gait in people with Parkinson disease (PD) and FoG. However, most physical rehabilitation does not include such challenges. The purpose was to determine (1) feasibility of a cognitively challenging Agility Boot Camp–Cognitive (ABC-C) program and (2) effects of this intervention on FoG, dual-task cost, balance, executive function, and functional connectivity. Methods. A total of 46 people with PD and FoG enrolled in this randomized crossover trial. Each participant had 6 weeks of ABC-C and Education interventions. Outcome measures were the following: FoG, perceived and objective measures; dual-task cost on gait; balance; executive function; and right supplementary motor area (SMA)–pedunculopontine nucleus (PPN) functional connectivity. Effect sizes were calculated. Results. ABC-C had high compliance (90%), with a 24% dropout rate. Improvements after exercise, revealed by moderate and large effect sizes, were observed for subject perception of FoG after exercise, dual-task cost on gait speed, balance, cognition (Scales for Outcomes in Parkinson’s disease–Cognition), and SMA-PPN connectivity. Conclusions. The ABC-C for people with PD and FoG is a feasible exercise program that has potential to improve FoG, balance, dual-task cost, executive function, and brain connectivity. The study provided effect sizes to help design future studies with more participants and longer duration to fully determine the potential to improve FoG.

Continuous monitoring of tremor with wearable wrist sensors during normal daily activities is more difficult than in a clinical setting when subjects perform prescribed activities because some normal daily activities resemble tremor, many normal movements contain frequency content that overlaps with the tremor frequency, and the tremor amplitude has a large dynamic range during normal daily activities. We describe a novel two-stage algorithm that offers improvement at discriminating tremor from other activities. Some of this improvement is attained by using prior domain knowledge that tremor occurs over a narrow range of frequencies for an individual, but the mean tremor frequency may vary significantly between individuals in a study population. We validated the algorithm in continuous recordings from people with Parkinson’s disease and matched control subjects. The algorithm has good face validity, a low rate of false positives on recordings from control subjects (< 1.1%), and good correspondence with the constancy of rest tremor as measured by this question on the MDS-UPDRS (ρ = 0.54).

People with Parkinson disease (PD) have particular difficulty recovering equilibrium in response to backward perturbations compared to other directions. The postural responses to external perturbations are weak and slow in PD (bradykinetic) compared to healthy older subjects but have normal onset latency. Muscle cocontraction and stiff joints impair postural responses to perturbations in people with PD. The inability to quickly change the pattern of postural response to changes in environmental context is unique to PD. Levodopa does not improve the strength or adaptation of postural responses. Deep brain stimulation (DBS) in subthalamic nucleus (STN) further impairs postural responses while DBS in internal Globus Pallidus (GPi) does not improve postural responses. Rehabilitation that includes responding to postural perturbations can improve postural responses in people with PD.

Wearable technology can improve sensitivity and reliability of assessment of domains of balance control in Parkinson disease (PD). In the future, ambulatory assessment of quality of mobility during daily life will also be used to better inform clinical decisions and improve patient-centered outcomes for clinical trials. New technologies that provide accurate, sensitive measures of balance control will also improve rehabilitation of balance disorders by allowing physical therapists to focus their therapy on the specific domains of balance affected in each individual. Body-worn sensors can also be used to provide real-time biofeedback to patients, or objective feedback to therapists, to improve balance control with training. Studies on transcranial direct electrical current to enhance neural plasticity and motor learning for balance and gait rehabilitation are needed. New medications to reduce motor fluctuations, improve the response to levodopa, and slow or stop progression of PD are currently being tested. The targets and types of electrical stimulation of the nervous system in PD will be changing in the future to focus on improving balance, improving freezing, and reducing falls. In the future, developments in wearable technology, rehabilitation, medication, and neural stimulation will lead to better balance in people with PD so they can live longer, active lives.

Balance issues should be addressed from the time of diagnosis of Parkinson disease (PD) because there are balance deficits at the beginning of the disease and the patient already has an elevated risk of falling. There is strong evidence that facility-based, directed balance exercises reduce falls. In addition, there is some evidence indicating exercise may have neuroprotective effects for PD. Levodopa partially improves some aspects of balance but may also worsen some aspects. This suggests that other neurologic systems are important to balance. Deep Brain Stimulation (DBS) generally does not help balance although it may improve straight ahead walking and bradykinesia of the limbs. Freezing of gait responds to various physical therapy tricks and sometimes to improvement in levodopa-induced motor fluctuations. Even when unassisted walking is impossible, it is important to maintain the patients’ mobility in the home and community. This usually requires wheelchairs and other assistive devices.

Freezing of gait (FoG) is a brief, episodic inability to step, with the perception that the feet are glued to the floor. FoG eventually affects a majority of people with Parkinson disease (PD) and is often associated with falls. PD with FoG shows more balance disorders than nonfreezers, particularly in anticipatory postural adjustments (APAs) and dynamic balance during gait. Both structural and functional abnormalities in widespread cortical and subcortical brain circuitry are present in people with FoG compared to nonfreezers, although it is difficult to control for presence of FoG and severity of disease. Levodopa is a partially effective treatment for FoG. DBS is generally not indicated for FoG and sometimes worsens it. External cueing can produce short-term improvement in prevention and reduce the duration of FoG events but shows habituation. Balance and gait and aerobic exercise have not resulted in long-term improvements in freezing of gait.

Background Identifying digital biomarkers of mobility is important for clinical trials in Parkinson's disease (PD). Objective To determine which digital outcome measures of mobility discriminate mobility in people with PD from healthy control (HC) subjects over a week of continuous monitoring. Methods We recruited 29 people with PD, and 27 age-matched HC subjects. Subjects were asked to wear three inertial sensors (Opal by APDM) attached to both feet and to the lumbar region, and a subset of subjects also wore two wrist sensors, for a week of continuous monitoring. We derived 43 digital outcome measures of mobility grouped into five domains. An Area Under Curve (AUC) was calculated for each digital outcome measures of mobility, and logistic regression employing a 'best subsets selection strategy' was used to find combinations of measures that discriminated mobility in PD from HC. Results Duration of recordings was 66±14 hours in the PD and 59±16 hours in the HC. Out of a total of 43 digital outcome measures of mobility, we found six digital outcome measures of mobility with AUC > 0.80. Turn angle (AUC = 0.89, 95% CI: 0.79-0.97) and swing time variability (AUC = 0.87, 95% CI: 0.75-0.96) were the most discriminative individual measures. Turning measures were most consistently selected via the best subsets strategy to discriminate people with PD from HC, followed by gait variability measures. Conclusion Clinical studies and clinical practice with digital biomarkers of daily life mobility in PD should include turning and variability measures.

Anticipatory postural adjustments (APAs) prior to step initiation and other voluntary movements are slower and hypometric in Parkinson disease (PD) from early in the disease. APAs are inflexible in PD. For example, people with PD show impaired ability to scale their APAs for step initiation with a wider stance compared to a narrow stance. Also, people with PD show APAs for protective steps, where controls do not use APAs prior to compensatory stepping to external perturbations. Levodopa improves APAs, although not to control values. Both GPi and STN DBS may be detrimental for APAs. Rehabilitation, especially in the form of external cueing or assisted transitions for APAs, may be beneficial, although the best type of rehabilitation for long-term effects is not clear.

Balance (posture) control has two main goals: postural equilibrium (stability) and postural orientation. Balance control has the following properties: the musculoskeletal system, antigravity postural tone, forward internal model of the body and world, coupling between posture and movement, and cognitive control of balance. Many different brain networks are involved in control of balance. The main roles of the basal ganglia in control of balance are: energization/scaling (vigor), 2) automatization, 3) posture-movement coupling, and 4) context-dependent adaptation. The main balance domains to assess are: standing balance, postural responses, postural transitions, dynamic balance during gait, and turning. Balance can be improved with practice.

Every person with Parkinson disease (PD) will face balance difficulties during the course of the disease. In fact, some balance and gait abnormalities appear very early in the disease. Balance is essential for mobility and is very important for quality of life, even more so than limb function. Balance problems lead to falls and falls are more common, more severe, and more life threatening in PD than other neurological diseases. Balance disturbances in Parkinson disease include multiple aspects of balance control, including standing balance, reactive postural responses, anticipatory postural adjustments prior to gait initiation, and dynamic balance during walking and turning. Balance disturbances are more than just a manifestation of motor dysfunction in PD. Cognitive, affective, sensory, and autonomic dysfunctions contribute to balance disorders in PD. Unfortunately, levodopa and DBS have both positive and negative effects on balance, so exercises focused on balance are an important contributor to treating balance problems in PD.