Feasibility and Proof-of-Concept of Delivering an Autonomous Music-Based Digital Walking Intervention to Persons with Parkinson's Disease in a Naturalistic Setting.

BACKGROUND: Reduced motor automaticity in Parkinson's disease (PD) negatively impacts the quality, intensity, and amount of daily walking. Rhythmic auditory stimulation (RAS), a clinical intervention shown to improve walking outcomes, has been limited by barriers associated with the need for ongoing clinician input. OBJECTIVE: To assess the feasibility, proof-of-concept, and preliminary clinical outcomes associated with delivering an autonomous music-based digital walking intervention based on RAS principles to persons with PD in a naturalistic setting. METHODS: Twenty-three persons with PD used the digital intervention independently for four weeks to complete five weekly 30-minute sessions of unsupervised, overground walking with music-based cues. The intervention progressed autonomously according to real-time gait sensing. Feasibility of independent use was assessed by examining participant adherence, safety, and experience. Intervention proof-of-concept was assessed by examining spatiotemporal metrics of gait quality, daily minutes of moderate intensity walking, and daily steps. Preliminary clinical outcomes were assessed following intervention completion. RESULTS: Participants completed 86.4% of sessions and 131.1% of the prescribed session duration. No adverse events were reported. Gait speed, stride length, and cadence increased within sessions, and gait variability decreased (p < 0.05). Compared to baseline, increased daily moderate intensity walking (mean Δ= +21.44 minutes) and steps (mean Δ= +3,484 steps) occurred on designated intervention days (p < 0.05). Quality of life, disease severity, walking endurance, and functional mobility were improved after four weeks (p < 0.05). CONCLUSIONS: Study findings supported the feasibility and potential clinical utility of delivering an autonomous digital walking intervention to persons with PD in a naturalistic setting.

Natural Walking Intensity in Persons With Parkinson Disease.

BACKGROUND AND PURPOSE: Few persons with Parkinson disease (PD) appear to engage in moderate-intensity walking associated with disease-modifying health benefits. How much time is spent walking at lower, yet still potentially beneficial, intensities is poorly understood. The purpose of this exploratory, observational study was to describe natural walking intensity in ambulatory persons with PD. METHODS: Accelerometer-derived real-world walking data were collected for more than 7 days at baseline from 82 participants enrolled in a PD clinical trial. Walking intensity was defined according to the number of steps in each active minute (1-19, 20-39, 40-59, 60-79, 80-99, or ≥100 steps). Daily minutes of walking and duration of the longest sustained walking bout were calculated at each intensity. Number of sustained 10 to 19, 20 to 29, and 30-minute bouts and greater at any intensity also were calculated. Values were analyzed in the context of physical activity guidelines. RESULTS: Most daily walking occurred at lower intensities (157.3 ± 58.1 min of 1-19 steps; 81.3 ± 32.6 min of 20-39 steps; 38.2 ± 21.3 min of 40-59 steps; 15.1 ± 11.5 min of 60-79 steps; 7.4 ± 7.0 min of 80-99 steps; 7.3 ± 9.6 min of ≥100 steps). The longest daily sustained walking bout occurred at the lowest intensity level (15.9 ± 5.2 min of 1-19 steps). Few bouts lasting 20 minutes and greater occurred at any intensity. DISCUSSION AND CONCLUSIONS: Despite relatively high daily step counts, participants tended to walk at remarkably low intensity, in bouts of generally short duration, with relatively few instances of sustained walking. The findings reinforced the need for health promotion interventions designed specifically to increase walking intensity.Video Abstract available for more insight from authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A426 ).

Narrowing the physiotherapy knowledge-practice gap: faculty training beyond the health sciences.

Physiotherapists seek to improve client movement and promote function within an individual's unique environmental and social realities. Despite this intention, there is a well-noted knowledge-practice gap, that is, therapists generally lack sufficient foundational preparation to effectively navigate societal challenges impacting contemporary healthcare. As one step toward addressing the issue, we propose an educational solution targeting current and future physiotherapy faculty, whose responsibilities for entry-level course development and curriculum design substantially impact student readiness for clinical practice. We propose that physiotherapy faculty trained via postprofessional education in a non-biomedical field (e.g. psychology, education, and philosophy) will be uniquely prepared to provide students with tools for dealing with complex social issues facing their clients; critical analysis skills; statistical and technological training; and a deeper theoretical and philosophical understanding of practice. Taken together, such interdisciplinary tools could help address the knowledge-practice gap for physiotherapists and promote the ongoing evolution of the profession in concert with contemporary healthcare. Physiotherapists who pursue interdisciplinary studies may more deeply understand the challenges faced by clinicians and may be well-positioned to leverage knowledge and methods in another scientific discipline to expand and transform the scope of solutions to these challenges.

Does clinically measured walking capacity contribute to real-world walking performance in Parkinson's disease?

OBJECTIVE: The study examined how clinically measured walking capacity contributes to real-world walking performance in persons with Parkinson's disease (PD). METHODS: Cross-sectional baseline data (n = 82) from a PD clinical trial were analyzed. The 6-Minute Walk Test (6MWT) and 10-Meter Walk Test (10MWT) were used to generate capacity metrics of walking endurance and fast gait speed, respectively. An activity monitor worn for seven days was used to generate performance metrics of mean daily steps and weekly moderate intensity walking minutes. Univariate linear regression analyses were used to examine associations between each capacity and performance measure in the full sample and less and more active subgroups. RESULTS: Walking capacity significantly contributed to daily steps in the full sample (endurance: R2=.13, p < .001; fast gait speed: R2=.07, p = .017) and in the less active subgroup (endurance: R2 =.09, p = .045). Similarly, walking capacity significantly contributed to weekly moderate intensity minutes in the full sample (endurance: R2=.13, p < .001; fast gait speed: R2=.09, p = .007) and less active subgroup (endurance: R2 = .25, p < .001; fast gait speed: R2 =.21, p = .007). Walking capacity did not significantly contribute to daily steps or moderate intensity minutes in the more active subgroup. CONCLUSIONS: Walking capacity contributed to, but explained a relatively small portion of the variance in, real-world walking performance. The contribution was somewhat greater in less active individuals. The study adds support to the idea that clinically measured walking capacity may have limited benefit for understanding real-world walking performance in PD. Factors beyond walking capacity may better account for actual walking behavior.

Are Mobile Persons With Parkinson Disease Necessarily More Active?

BACKGROUND AND PURPOSE: Walking activity in persons with Parkinson disease (PD) is important for preventing functional decline. The contribution of walking activity to home and community mobility in PD is poorly understood. METHODS: Cross-sectional baseline data (N = 69) were analyzed from a randomized controlled PD trial. The Life-Space Assessment (LSA) quantified the extent, frequency, and independence across 5 expanding levels of home and community mobility, producing individual subscores and a total score. Two additional summed scores were used to represent mobility within (Levels 1-3) and beyond (Levels 4-5) neighborhood limits. An accelerometer measured walking activity for 7 days. Regression and correlation analyses evaluated relationships between daily steps and mobility scores. Mann-Whitney U tests secondarily compared differences in mobility scores between the active and sedentary groups. RESULTS: Walking activity contributed significantly to the summed Level 1-3 score (ß = 0.001, P = 0.004) but not to the summed Level 4-5 (ß = 0.001, P = 0.33) or total (ß = 0.002, P = 0.07) scores. Walking activity was significantly related to Level 1 (ρ = 0.336, P = 0.005), Level 2 (ρ = 0.307, P = 0.010), and Level 3 (ρ = 0.314, P = 0.009) subscores. Only the summed Level 1-3 score (P = 0.030) was significantly different between the active and sedentary groups. DISCUSSION AND CONCLUSIONS: Persons with PD who demonstrated greater mobility beyond the neighborhood were not necessarily more active; walking activity contributed more so to home and neighborhood mobility. Compared with LSA total score, the Level 1-3 summed score may be a more useful participation-level measure for assessing the impact of changes in walking activity.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A349).

An Open Resource for Non-human Primate Optogenetics.

Optogenetics has revolutionized neuroscience in small laboratory animals, but its effect on animal models more closely related to humans, such as non-human primates (NHPs), has been mixed. To make evidence-based decisions in primate optogenetics, the scientific community would benefit from a centralized database listing all attempts, successful and unsuccessful, of using optogenetics in the primate brain. We contacted members of the community to ask for their contributions to an open science initiative. As of this writing, 45 laboratories around the world contributed more than 1,000 injection experiments, including precise details regarding their methods and outcomes. Of those entries, more than half had not been published. The resource is free for everyone to consult and contribute to on the Open Science Framework website. Here we review some of the insights from this initial release of the database and discuss methodological considerations to improve the success of optogenetic experiments in NHPs.

Organization of Corollary Discharge Neurons in Monkey Medial Dorsal Thalamus.

A corollary discharge (CD) is a copy of a neuronal command for movement sent to other brain regions to inform them of the impending movement. In monkeys, a circuit from superior colliculus (SC) through medial-dorsal nucleus of the thalamus (MD) to frontal eye field (FEF) carries such a CD for saccadic eye movements. This circuit provides the clearest example of such internal monitoring reaching cerebral cortex. In this report we first investigated the functional organization of the critical MD relay by systematically recording neurons within a grid of penetrations. In two male rhesus macaque monkeys (Macaca mulatta), we found that lateral MD neurons carrying CD signals discharged before saccades to ipsilateral as well as contralateral visual fields instead of just contralateral fields, often had activity over large movement fields, and had activity from both central and peripheral visual fields. Each of these characteristics has been found in FEF, but these findings indicate that these characteristics are already present in the thalamus. These characteristics show that the MD thalamic relay is not passive but instead assembles inputs from the SC before transmission to cortex. We next determined the exact location of the saccade-related CD neurons using the grid of penetrations. The neurons occupy an anterior-posterior band at the lateral edge of MD, and we established this band in stereotaxic coordinates to facilitate future study of CD neurons. These observations reveal both the organizational features of the internal CD signals within the thalamus, and the location of the thalamic relay for those signals.SIGNIFICANCE STATEMENT A corollary discharge (CD) circuit within the brain keeps an internal record of physical movements. In monkeys and humans, one such CD keeps track of rapid eye movements, and in monkeys, a circuit carrying this CD extends from midbrain to cerebral cortex through a relay in the thalamus. This circuit provides guidance for eye movements, contributes to stable visual perception, and when defective, might be related to difficulties that schizophrenic patients have in recognizing their own movements. This report facilitates the comparison of the circuit in monkeys and humans, particularly for comparison of the location of the thalamic relay in monkeys and in humans.

Design of the WHIP-PD study: a phase II, twelve-month, dual-site, randomized controlled trial evaluating the effects of a cognitive-behavioral approach for promoting enhanced walking activity using mobile health technology in people with Parkinson-disease.

BACKGROUND: Parkinson disease (PD) is a debilitating and chronic neurodegenerative disease resulting in ambulation difficulties. Natural walking activity often declines early in disease progression despite the relative stability of motor impairments. In this study, we propose a paradigm shift with a "connected behavioral approach" that targets real-world walking using cognitive-behavioral training and mobile health (mHealth) technology. METHODS/DESIGN: The Walking and mHealth to Increase Participation in Parkinson Disease (WHIP-PD) study is a twelve-month, dual site, two-arm, randomized controlled trial recruiting 148 participants with early to mid-stage PD. Participants will be randomly assigned to connected behavioral or active control conditions. Both conditions will include a customized program of goal-oriented walking, walking-enhancing strengthening exercises, and eight in-person visits with a physical therapist. Participants in the connected behavioral condition also will (1) receive cognitive-behavioral training to promote self-efficacy for routine walking behavior and (2) use a mHealth software application to manage their program and communicate remotely with their physical therapist. Active control participants will receive no cognitive-behavioral training and manage their program on paper. Evaluations will occur at baseline, three-, six-, and twelve-months and include walking assessments, self-efficacy questionnaires, and seven days of activity monitoring. Primary outcomes will include the change between baseline and twelve months in overall amount of walking activity (mean number of steps per day) and amount of moderate intensity walking activity (mean number of minutes per day in which > 100 steps were accumulated). Secondary outcomes will include change in walking capacity as measured by the six-minute walk test and ten-meter walk test. We also will examine if self-efficacy mediates change in amount of walking activity and if change in amount of walking activity mediates change in walking capacity. DISCUSSION: We expect this study to show the connected behavioral approach will be more effective than the active control condition in increasing the amount and intensity of real-world walking activity and improving walking capacity. Determining effective physical activity interventions for persons with PD is important for preserving mobility and essential for maintaining quality of life. Clinical trials registration NCT03517371, May 7, 2018. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03517371. Date of registration: May 7, 2018. Protocol version: Original.

Comparative Effectiveness of mHealth-Supported Exercise Compared With Exercise Alone for People With Parkinson Disease: Randomized Controlled Pilot Study.

Background: Declining physical activity commonly occurs in people with Parkinson disease (PD) and contributes to reduced functional capacity and quality of life. Objective: The purpose of this study was to explore the preliminary effectiveness, safety, and acceptability of a mobile health (mHealth)-mediated exercise program designed to promote sustained physical activity in people with PD. Design: This was a 12-month single-blind (assessor), pilot, comparative-effectiveness, randomized controlled study. Methods: An mHealth-mediated exercise program (walking with a pedometer plus engagement in planned exercise supported by a mobile health application) was compared over 1 year with an active control condition (walking with a pedometer and exercise only). There were 51 participants in a community setting with mild-to-moderately severe (Hoehn and Yahr stages 1-3) idiopathic PD. Daily steps and moderate-intensity minutes were measured using a step activity monitor for 1 week at baseline and again at 12 months. Secondary outcomes included the 6-Minute Walk Test, Parkinson Disease Questionnaire 39 mobility domain, safety, acceptability, and adherence. Results: Both groups increased daily steps, moderate-intensity minutes, and 6-Minute Walk Test, with no statistically significant between-group differences observed. In the less active subgroup, changes in daily steps and moderate-intensity minutes were clinically meaningful. An improvement in the Parkinson Disease Questionnaire 39 mobility score favored mHealth in the overall comparison and was statistically and clinically meaningful in the less active subgroup. Limitations: The limitation of the current study was the small sample size. Conclusions: Both groups improved physical activity compared with expected activity decline over 1 year. The addition of the mHealth app to the exercise intervention appeared to differentially benefit the more sedentary participants. Further study in a larger group of people with low activity at baseline is needed.

Visual Responses in FEF, Unlike V1, Primarily Reflect When the Visual Context Renders a Receptive Field Salient.

When light falls within a neuronal visual receptive field (RF) the resulting activity is referred to as the visual response. Recent work suggests this activity is in response to both the visual stimulation and the abrupt appearance, or salience, of the presentation. Here we present a novel method for distinguishing the two, based on the timing of random and nonrandom presentations. We examined these contributions in frontal eye field (FEF; N = 51) and as a comparison, an early stage in the primary visual cortex (V1; N = 15) of male monkeys (Macaca mulatta). An array of identical stimuli was presented within and outside the neuronal RF while we manipulated salience by varying the time between stimulus presentations. We hypothesized that the rapid presentation would reduce salience (the sudden appearance within the visual field) of a stimulus at any one location, and thus decrease responses driven by salience in the RF. We found that when the interstimulus interval decreased from 500 to 16 ms there was an approximate 79% reduction in the FEF response compared with an estimated 17% decrease in V1. This reduction in FEF response for rapid presentation was evident even when the random sequence preceding a stimulus did not stimulate the RF for 500 ms. The time course of these response changes in FEF suggest that salience is represented much earlier (<100 ms following stimulus onset) than previously estimated. Our results suggest that the contribution of salience dominates at higher levels of the visual system.SIGNIFICANCE STATEMENT The neuronal responses in early visual processing [e.g., primary visual cortex (V1)] reflect primarily the retinal stimulus. Processing in higher visual areas is modulated by a combination of the visual stimulation and contextual factors, such as salience, but identifying these components separately has been difficult. Here we quantified these contributions at a late stage of visual processing [frontal eye field (FEF)] and as a comparison, an early stage in V1. Our results suggest that as visual information continues through higher levels of processing the neural responses are no longer driven primarily by the visual stimulus in the receptive field, but by the broader context that stimulus defines-very different from current views about visual signals in FEF.

Adaptation of postural recovery responses to a vestibular sensory illusion in individuals with Parkinson disease and healthy controls.

BACKGROUND: The ability to adapt postural responses to sensory illusions diminishes with age and is further impaired by Parkinson disease. However, limited information exists regarding training-related adaptions of sensory reweighting in these populations. METHODS: This study sought to determine whether Parkinson disease or age would differentially affect acute postural recovery or adaptive postural responses to novel or repeated exposure to sensory illusions using galvanic vestibular stimulation during quiet stance. FINDINGS: Acutely, individuals with Parkinson disease demonstrated larger center of pressure coefficient of variation compared to controls. Unlike individuals with Parkinson disease and asymptomatic older adults, healthy young adults acutely demonstrated a reduction in Sample Entropy to the sensory illusion. Following a period of consolidation Sample Entropy increased in the healthy young group, which coincided with a decreased center of pressure coefficient of variation. Similar changes were not observed in the Parkinson disease or older adult groups. INTERPRETATION: Taken together, these results suggest that young adults learn to adapt to vestibular illusion in a more robust manner than older adults or those with Parkinson disease. Further investigation into the nature of this adaptive difference is warranted.

Multifractality, Interactivity, and the Adaptive Capacity of the Human Movement System: A Perspective for Advancing the Conceptual Basis of Neurologic Physical Therapy.

BACKGROUND AND PURPOSE: Physical therapists seek to optimize movement as a means of reducing disability and improving health. The short-term effects of interventions designed to optimize movement ultimately are intended to be adapted for use across various future patterns of behavior, in potentially unpredictable ways, with varying frequency, and in the context of multiple tasks and environmental conditions. In this perspective article, we review and discuss the implications of recent evidence that optimal movement variability, which previously had been associated with adaptable motor behavior, contains a specific complex nonlinear feature known as "multifractality." SUMMARY OF KEY POINTS: Multifractal movement fluctuation patterns reflect robust physiologic interactivity occurring within the movement system across multiple time scales. Such patterns provide conceptual support for the idea that patterns of motor behavior occurring in the moment are inextricably linked in complex, physiologic ways to patterns of motor behavior occurring over much longer periods. The human movement system appears to be particularly tuned to multifractal fluctuation patterns and exhibits the ability to reorganize its output in response to external stimulation embedded with multifractal features. RECOMMENDATIONS FOR CLINICAL PRACTICE: As a fundamental feature of human movement, multifractality opens new avenues for conceptualizing the link between physiologic interactivity and adaptive capacity. Preliminary evidence supporting the positive influence of multifractal rhythmic auditory stimulation on the gait patterns of individuals with Parkinson disease is used to illustrate how physical therapy interventions might be devised to specifically target the adaptive capacity of the human movement system.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A183).

Exploring the Effects of Using an Oral Appliance to Reduce Movement Dysfunction in an Individual With Parkinson Disease: A Single-Subject Design Study.

BACKGROUND AND PURPOSE: Clinical reports suggest that wearing an oral appliance can improve the gait and balance of an individual with Parkinson disease (PD). Our primary purpose was to systematically explore this effect using a single-subject study design and quantitative motion analysis. Secondarily, we sought to examine the quality-of-life outcomes following 1-month of routine oral appliance wear. METHODS: The participant was a 73-year-old ambulatory man with mid-stage PD. Using an A-B-A design, for which a custom-made oral appliance served as the intervention, kinematic and kinetic data were captured during performance of Four Square Step Test, serpentine walk, and tandem walk tasks. Grip strength was quantified with a dynamometer. Quality-of-life outcomes were collected after 1 month of appliance wear using the Parkinson Disease Questionnaire-39 (PDQ-39). Perceived changes in balance, mobility, and quality of life were captured from the participant using an 11-point Global Rate of Change (GRC) scale. RESULTS: Changes in mobility, postural control, and grip strength during appliance wear were suggestive of reduced movement dysfunction. The PDQ-39 revealed a significant improvement in quality of life, primarily related to increased emotional well-being, decreased stigma, and increased communication. GRC scores indicated a clinically significant improvement in ease of movement in the community (+3), ease of movement during the performance of activities of daily living (+4), and in standing balance while performing activities of daily living (+4). DISCUSSION AND CONCLUSIONS: Study findings provided quantitative evidence supporting the effectiveness of oral appliance wear for reducing movement dysfunction in a patient with mid-stage PD.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A155).

A circuit for saccadic suppression in the primate brain.

Saccades should cause us to see a blur as the eyes sweep across a visual scene. Specific brain mechanisms prevent this by producing suppression during saccades. Neuronal correlates of such suppression were first established in the visual superficial layers of the superior colliculus (SC) and subsequently have been observed in cortical visual areas, including the middle temporal visual area (MT). In this study, we investigated suppression in a recently identified circuit linking visual SC (SCs) to MT through the inferior pulvinar (PI). We examined responses to visual stimuli presented just before saccades to reveal a neuronal correlate of suppression driven by a copy of the saccade command, referred to as a corollary discharge. We found that visual responses were similarly suppressed in SCs, PI, and MT. Within each region, suppression of visual responses occurred with saccades into both visual hemifields, but only in the contralateral hemifield did this suppression consistently begin before the saccade (~100 ms). The consistency of the signal along the circuit led us to hypothesize that the suppression in MT was influenced by input from the SC. We tested this hypothesis in one monkey by inactivating neurons within the SC and found evidence that suppression in MT depends on corollary discharge signals from motor SC (SCi). Combining these results with recent findings in rodents, we propose a complete circuit originating with corollary discharge signals in SCi that produces suppression in visual SCs, PI, and ultimately, MT cortex.NEW & NOTEWORTHY A fundamental puzzle in visual neuroscience is that we frequently make rapid eye movements (saccades) but seldom perceive the visual blur accompanying each movement. We investigated neuronal correlates of this saccadic suppression by recording from and perturbing a recently identified circuit from brainstem to cortex. We found suppression at each stage, with evidence that it was driven by an internally generated signal. We conclude that this circuit contributes to neuronal suppression of visual signals during eye movements.

Are the average gait speeds during the 10meter and 6minute walk tests redundant in Parkinson disease?

We investigated the relationships between average gait speed collected with the 10Meter Walk Test (Comfortable and Fast) and 6Minute Walk Test (6MWT) in 346 people with Parkinson disease (PD) and how the relationships change with increasing disease severity. Pearson correlation and linear regression analyses determined relationships between 10Meter Walk Test and 6MWT gait speed values for the entire sample and for sub-samples stratified by Hoehn & Yahr (H&Y) stage I (n=53), II (n=141), III (n=135) and IV (n=17). We hypothesized that redundant tests would be highly and significantly correlated (i.e. r>0.70, p<0.05) and would have a linear regression model slope of 1 and intercept of 0. For the entire sample, 6MWT gait speed was significantly (p<0.001) related to the Comfortable 10 Meter Walk Test (r=0.75) and Fast 10Meter Walk Test (r=0.79) gait speed, with 56% and 62% of the variance in 6MWT gait speed explained, respectively. The regression model of 6MWT gait speed predicted by Comfortable 10 Meter Walk gait speed produced slope and intercept values near 1 and 0, respectively, especially for participants in H&Y stages II-IV. In contrast, slope and intercept values were further from 1 and 0, respectively, for the Fast 10Meter Walk Test. Comfortable 10 Meter Walk Test and 6MWT gait speeds appeared to be redundant in people with moderate to severe PD, suggesting the Comfortable 10 Meter Walk Test can be used to estimate 6MWT distance in this population.

Obtaining Reliable Estimates of Ambulatory Physical Activity in People with Parkinson's Disease.

We determined the number of days required, and whether to include weekdays and/or weekends, to obtain reliable measures of ambulatory physical activity in people with Parkinson's disease (PD). Ninety-two persons with PD wore a step activity monitor for seven days. The number of days required to obtain a reliable estimate of daily activity was determined from the mean intraclass correlation (ICC2,1) for all possible combinations of 1-6 consecutive days of monitoring. Two days of monitoring were sufficient to obtain reliable daily activity estimates (ICC2,1 > 0.9). Amount (p = 0.03) but not intensity (p = 0.13) of ambulatory activity was greater on weekdays than weekends. Activity prescription based on amount rather than intensity may be more appropriate for people with PD.

Identifying clinical measures that most accurately reflect the progression of disability in Parkinson disease.

INTRODUCTION: The temporal relationship between disease and disability progression in Parkinson disease (PD) is not well understood. Our objective was to describe the natural, multidimensional trajectory of disability in persons with PD over a two-year period. METHODS: We conducted a multi-center, prospective cohort study involving four institutions. Data were collected at baseline and at 6-month intervals over 2 years using standardized clinical tests representing three World Health Organization defined disability domains: impairment, activity limitation, and participation restriction. Unadjusted mixed effects growth models characterized trajectories of disability in the three disability domains. The data set was analyzed using restricted maximum likelihood (REML) estimation. Standardized estimates of change were also computed using Cohen's d for each measure. RESULTS: Of the 266 enrolled participants, we analysed data from individuals who participated in at least 3 assessments (n = 207, 79%). Rates of disability progression over the 2-year period differed across domains. Moderate effects were detected for motor impairment (d = .28) and walking-related activity limitation (gait-related balance (d = .31); gait speed (d = .30)). Marginal effects were noted for upper extremity-related activity limitation (d = .11) and health-related quality of life participation restriction (d = .08). CONCLUSIONS: The natural trajectory of walking-related activity limitation was the most potent indicator of evolving disability, suggesting that routine assessment of walking and periodic rehabilitation is likely to be warranted for many persons with PD. Natural trajectories of disability provide important comparison data for future intervention studies.

Saccadic Corollary Discharge Underlies Stable Visual Perception.

Saccadic eye movements direct the high-resolution foveae of our retinas toward objects of interest. With each saccade, the image jumps on the retina, causing a discontinuity in visual input. Our visual perception, however, remains stable. Philosophers and scientists over centuries have proposed that visual stability depends upon an internal neuronal signal that is a copy of the neuronal signal driving the eye movement, now referred to as a corollary discharge (CD) or efference copy. In the old world monkey, such a CD circuit for saccades has been identified extending from superior colliculus through MD thalamus to frontal cortex, but there is little evidence that this circuit actually contributes to visual perception. We tested the influence of this CD circuit on visual perception by first training macaque monkeys to report their perceived eye direction, and then reversibly inactivating the CD as it passes through the thalamus. We found that the monkey's perception changed; during CD inactivation, there was a difference between where the monkey perceived its eyes to be directed and where they were actually directed. Perception and saccade were decoupled. We established that the perceived eye direction at the end of the saccade was not derived from proprioceptive input from eye muscles, and was not altered by contextual visual information. We conclude that the CD provides internal information contributing to the brain's creation of perceived visual stability. More specifically, the CD might provide the internal saccade vector used to unite separate retinal images into a stable visual scene. SIGNIFICANCE STATEMENT: Visual stability is one of the most remarkable aspects of human vision. The eyes move rapidly several times per second, displacing the retinal image each time. The brain compensates for this disruption, keeping our visual perception stable. A major hypothesis explaining this stability invokes a signal within the brain, a corollary discharge, that informs visual regions of the brain when and where the eyes are about to move. Such a corollary discharge circuit for eye movements has been identified in macaque monkey. We now show that selectively inactivating this brain circuit alters the monkey's visual perception. We conclude that this corollary discharge provides a critical signal that can be used to unite jumping retinal images into a consistent visual scene.

Two-Year Trajectory of Fall Risk in People With Parkinson Disease: A Latent Class Analysis.

OBJECTIVE: To examine fall risk trajectories occurring naturally in a sample of individuals with early to middle stage Parkinson disease (PD). DESIGN: Latent class analysis, specifically growth mixture modeling (GMM), of longitudinal fall risk trajectories. SETTING: Assessments were conducted at 1 of 4 universities. PARTICIPANTS: Community-dwelling participants with PD of a longitudinal cohort study who attended at least 2 of 5 assessments over a 2-year follow-up period (N=230). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Fall risk trajectory (low, medium, or high risk) and stability of fall risk trajectory (stable or fluctuating). Fall risk was determined at 6 monthly intervals using a simple clinical tool based on fall history, freezing of gait, and gait speed. RESULTS: The GMM optimally grouped participants into 3 fall risk trajectories that closely mirrored baseline fall risk status (P=.001). The high fall risk trajectory was most common (42.6%) and included participants with longer and more severe disease and with higher postural instability and gait disability (PIGD) scores than the low and medium fall risk trajectories (P<.001). Fluctuating fall risk (posterior probability <0.8 of belonging to any trajectory) was found in only 22.6% of the sample, most commonly among individuals who were transitioning to PIGD predominance. CONCLUSIONS: Regardless of their baseline characteristics, most participants had clear and stable fall risk trajectories over 2 years. Further investigation is required to determine whether interventions to improve gait and balance may improve fall risk trajectories in people with PD.

Balance differences in people with Parkinson disease with and without freezing of gait.

BACKGROUND: Freezing of gait (FOG) is a relatively common and remarkably disabling impairment associated with Parkinson disease (PD). Laboratory-based measures indicate that individuals with FOG (PD+FOG) have greater balance deficits than those without FOG (PD-FOG). Whether such differences also can be detected using clinical balance tests has not been investigated. We sought to determine if balance and specific aspects of balance, measured using Balance Evaluation Systems Test (BESTest), differs between PD+FOG and PD-FOG. Furthermore, we aimed to determine if time-efficient clinical balance measures (i.e. Mini-BESTest, Berg Balance Scale (BBS)) could detect balance differences between PD+FOG and PD-FOG. METHODS: Balance of 78 individuals with PD, grouped as either PD+FOG (n=32) or PD-FOG (n=46), was measured using the BESTest, Mini-BESTest, and BBS. Between-groups comparisons were conducted for these measures and for the six sections of the BESTest using analysis of covariance. A PD composite score was used as a covariate. RESULTS: Controlling for motor sign severity, PD duration, and age, PD+FOG had worse balance than PD-FOG when measured using the BESTest (p=0.008, F=7.35) and Mini-BESTest (p=0.002, F=10.37), but not the BBS (p=0.27, F=1.26). BESTest section differences were noted between PD+FOG and PD-FOG for reactive postural responses (p<0.001, F=14.42) and stability in gait (p=0.003, F=9.18). CONCLUSIONS: The BESTest and Mini-BESTest, which specifically assessed reactive postural responses and stability in gait, were more likely than the BBS to detect differences in balance between PD+FOG and PD-FOG. Because it is more time efficient to administer, the Mini-BESTest may be the preferred tool for assessing balance deficits associated with FOG.