A Visual and Narrative Timeline Review of Spinal Cord Stimulation Technology and US Food and Drug Administration Milestones.

OBJECTIVES: The aim of this study was to present key technologic and regulatory milestones in spinal cord stimulation (SCS) for managing chronic pain on a narrative timeline with visual representation, relying on original sources to the extent possible. MATERIALS AND METHODS: We identified technical advances in SCS that facilitated and enhanced treatment on the basis of scientific publications and approvals from the United States (US) Food and Drug Administration (FDA). We presented milestones limited to first use in key indications and in the context of new technology validation. We focused primarily on pain management, but other indications (eg, motor disorder in multiple sclerosis) were included when they affected technology development. RESULTS: We developed a comprehensive visual and narrative timeline of SCS technology and US FDA milestones. Since its conception in the 1960s, the science and technology of SCS neuromodulation have continuously evolved. Advances span lead design (from paddle-type to percutaneous, and increased electrode contacts) and stimulator technology (from wireless power to internally powered and rechargeable, with miniaturized components, and programmable multichannel devices), with expanding stimulation program flexibility (such as burst and kilohertz stimulation frequencies), as well as usage features (such as remote programming and magnetic resonance imaging conditional compatibility). CONCLUSIONS: This timeline represents the evolution of SCS technology alongside expanding FDA-approved indications for use.

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Effects of 2 Years of Exercise on Gait Impairment in People With Parkinson Disease: The PRET-PD Randomized Trial.

BACKGROUND AND PURPOSE: This study presents a secondary analysis from the Progressive Resistance Exercise Training in Parkinson Disease (PRET-PD) trial investigating the effects of progressive resistance exercise (PRE) and a Parkinson disease (PD)-specific multimodal exercise program, modified Fitness Counts (mFC), on spatial, temporal, and stability-related gait impairments in people with PD. METHODS: Forty-eight people with PD were randomized to participate in PRE or mFC 2 times a week for 24 months; 38 completed the study. Gait velocity, stride length, cadence, and double-support time were measured under 4 walking conditions (off-/on-medication, comfortable/fast speed). Ankle strength was also measured off- and on-medication. Twenty-four healthy controls provided comparison data at one time point. RESULTS: At 24 months, there were no significant differences between exercise groups. Both groups improved fast gait velocity off-medication, cadence in all conditions, and plantarflexion strength off-/on-medication. Both groups with PD had more gait measures that approximated the healthy controls at 24 months than at baseline. Plantarflexion strength was significantly associated with gait velocity and stride length in people with PD at baseline and 24 months, but changes in strength were not associated with changes in gait. DISCUSSION AND CONCLUSIONS: Twenty-four months of PRE and mFC were associated with improved off-medication fast gait velocity and improved cadence in all conditions, which is important because temporal gait measures can be resistant to medications. Spatial and stability-related measures were resistant to long-term improvements, but did not decline over 24 months. Strength gains did not appear to transfer to gait.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A161).

Factors Associated With Ambulatory Activity in De Novo Parkinson Disease.

BACKGROUND AND PURPOSE: Objective ambulatory activity during daily living has not been characterized for people with Parkinson disease prior to initiation of dopaminergic medication. Our goal was to characterize ambulatory activity based on average daily step count and examine determinants of step count in nonexercising people with de novo Parkinson disease. METHODS: We analyzed baseline data from a randomized controlled trial, which excluded people performing regular endurance exercise. Of 128 eligible participants (mean ± SD = 64.3 ± 8.6 years), 113 had complete accelerometer data, which were used to determine daily step count. Multiple linear regression was used to identify factors associated with average daily step count over 10 days. Candidate explanatory variable categories were (1) demographics/anthropometrics, (2) Parkinson disease characteristics, (3) motor symptom severity, (4) nonmotor and behavioral characteristics, (5) comorbidities, and (6) cardiorespiratory fitness. RESULTS: Average daily step count was 5362 ± 2890 steps per day. Five factors explained 24% of daily step count variability, with higher step count associated with higher cardiorespiratory fitness (10%), no fear/worry of falling (5%), lower motor severity examination score (4%), more recent time since Parkinson disease diagnosis (3%), and the presence of a cardiovascular condition (2%). DISCUSSION AND CONCLUSIONS: Daily step count in nonexercising people recruited for this intervention trial with de novo Parkinson disease approached sedentary lifestyle levels. Further study is warranted for elucidating factors explaining ambulatory activity, particularly cardiorespiratory fitness, and fear/worry of falling. Clinicians should consider the costs and benefits of exercise and activity behavior interventions immediately after diagnosis of Parkinson disease to attenuate the health consequences of low daily step count.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A170).

Progressive resistance exercise restores some properties of the triphasic EMG pattern and improves bradykinesia: the PRET-PD randomized clinical trial.

In Parkinson's disease (PD), the characteristic triphasic agonist and antagonist muscle activation pattern during ballistic movement is impaired: the number of agonist muscle bursts is increased, and the amplitudes of the agonist and antagonist bursts are reduced. The breakdown of the triphasic electromyographic (EMG) pattern has been hypothesized to underlie bradykinesia in PD. Progressive resistance exercise has been shown to improve clinical measures of bradykinesia, but it is not clear whether the benefits for bradykinesia are accompanied by changes in agonist and antagonist muscle activity. This study examined the spatiotemporal changes in agonist and antagonist muscle activity following 24 mo of progressive resistance exercise and the combined relationship between spatiotemporal muscle activity and strength measures and upper limb bradykinesia. We compared the effects of progressive resistance exercise training (PRET) with a nonprogressive exercise intervention, modified Fitness Counts (mFC), in patients with PD. We randomized 48 participants with mild-to-moderate PD to mFC or PRET. At the study endpoint of 24 mo, participants randomized to PRET compared with mFC had significantly faster movement velocity, accompanied by significant increases in the duration, magnitude, and magnitude normalized to duration of the 1st agonist burst and fewer number of agonist bursts before peak velocity. The antagonist muscle activity was increased relative to baseline but did not differ between groups. Spatiotemporal EMG muscle activity and muscle strength were significantly associated with upper limb bradykinesia. These findings demonstrate that progressive resistance exercise improves upper limb movement velocity and restores some aspects of the triphasic EMG pattern.

Exercise improves cognition in Parkinson's disease: The PRET-PD randomized, clinical trial.

BACKGROUND: This article reports on the findings of the effect of two structured exercise interventions on secondary cognitive outcomes that were gathered as part of the Progressive Resistance Exercise Training in Parkinson's disease (PD) randomized, controlled trial. METHODS: This study was a prospective, parallel-group, single-center trial. Fifty-one nondemented patients with mild-to-moderate PD were randomly assigned either to modified Fitness Counts (mFC) or to Progressive Resistance Exercise Training (PRET) and were followed for 24 months. Cognitive outcomes were the Digit Span, Stroop, and Brief Test of Attention (BTA). RESULTS: Eighteen patients in mFC and 20 patients in PRET completed the trial. At 12 and at 24 months, no differences between groups were observed. At 12 months, relative to baseline, mFC improved on the Digit Span (estimated change: 0.3; interquartile range: 0, 0.7; P = 0.04) and Stroop (0.3; 0, 0.6; P = 0.04), and PRET improved only on the Digit Span (0.7; 0.3, 1; P < 0.01). At 24 months, relative to baseline, mFC improved on the Digit Span (0.7; 0.3, 1.7; P < 0.01) and Stroop (0.3; 0.1, 0.5; P = 0.03), whereas PRET improved on the Digit Span (0.5; 0.2, 0.8; P < 0.01), Stroop (0.2; -0.1, 0.6; P = 0.048), and BTA (0.3; 0, 0.8; P = 0.048). No neurological or cognitive adverse events were observed. CONCLUSIONS: This study provides class IV level of evidence that 24 months of PRET or mFC may improve attention and working memory in nondemented patients with mild-to-moderate Parkinson's disease.

Transient shifts in frontal and parietal circuits scale with enhanced visual feedback and changes in force variability and error.

When subjects perform a learned motor task with increased visual gain, error and variability are reduced. Neuroimaging studies have identified a corresponding increase in activity in parietal cortex, premotor cortex, primary motor cortex, and extrastriate visual cortex. Much less is understood about the neural processes that underlie the immediate transition from low to high visual gain within a trial. This study used 128-channel electroencephalography to measure cortical activity during a visually guided precision grip task, in which the gain of the visual display was changed during the task. Force variability during the transition from low to high visual gain was characterized by an inverted U-shape, whereas force error decreased from low to high gain. Source analysis identified cortical activity in the same structures previously identified using functional magnetic resonance imaging. Source analysis also identified a time-varying shift in the strongest source activity. Superior regions of the motor and parietal cortex had stronger source activity from 300 to 600 ms after the transition, whereas inferior regions of the extrastriate visual cortex had stronger source activity from 500 to 700 ms after the transition. Force variability and electrical activity were linearly related, with a positive relation in the parietal cortex and a negative relation in the frontal cortex. Force error was nonlinearly related to electrical activity in the parietal cortex and frontal cortex by a quadratic function. This is the first evidence that force variability and force error are systematically related to a time-varying shift in cortical activity in frontal and parietal cortex in response to enhanced visual gain.

A two-year randomized controlled trial of progressive resistance exercise for Parkinson's disease.

The effects of progressive resistance exercise (PRE) on the motor signs of Parkinson's disease have not been studied in controlled trials. The objective of the current trial was to compare 6-, 12-, 18-, and 24-month outcomes of patients with Parkinson's disease who received PRE with a stretching, balance, and strengthening exercise program. The authors conducted a randomized controlled trial between September 2007 and July 2011. Pairs of patients matched by sex and off-medication scores on the Unified Parkinson's Disease Rating Scale, motor subscale (UPDRS-III), were randomly assigned to the interventions with a 1:1 allocation ratio. The PRE group performed a weight-lifting program. The modified fitness counts (mFC) group performed a stretching, balance, and strengthening exercise program. Patients exercised 2 days per week for 24 months at a gym. A personal trainer directed both weekly sessions for the first 6 months and 1 weekly session after 6 months. The primary outcome was the off-medication UPDRS-III score. Patients were followed for 24 months at 6-month intervals. Of 51 patients, 20 in the PRE group and 18 in the mFC group completed the trial. At 24 months, the mean off-medication UPDRS-III score decreased more with PRE than with mFC (mean difference, -7.3 points; 95% confidence interval, -11.3 to -3.6; P<0.001). The PRE group had 10 adverse events, and the mFC group had 7 adverse events. PRE demonstrated a statistically and clinically significant reduction in UPDRS-III scores compared with mFC and is recommended as a useful adjunct therapy to improve Parkinsonian motor signs. © 2013 Movement Disorder Society.

Multi-scale multi-physics model of brain interstitial water flux by transcranial Direct Current Stimulation.

Objective. Transcranial direct current stimulation (tDCS) generates sustained electric fields in the brain, that may be amplified when crossing capillary walls (across blood-brain barrier, BBB). Electric fields across the BBB may generate fluid flow by electroosmosis. We consider that tDCS may thus enhance interstitial fluid flow.Approach. We developed a modeling pipeline novel in both (1) spanning the mm (head),µm (capillary network), and then nm (down to BBB tight junction (TJ)) scales; and (2) coupling electric current flow to fluid current flow across these scales. Electroosmotic coupling was parametrized based on prior measures of fluid flow across isolated BBB layers. Electric field amplification across the BBB in a realistic capillary network was converted to volumetric fluid exchange.Main results. The ultrastructure of the BBB results in peak electric fields (per mA of applied current) of 32-63Vm-1across capillary wall and >1150Vm-1in TJs (contrasted with 0.3Vm-1in parenchyma). Based on an electroosmotic coupling of 1.0 × 10-9- 5.6 × 10-10m3s-1m2perVm-1, peak water fluxes across the BBB are 2.44 × 10-10- 6.94 × 10-10m3s-1m2, with a peak 1.5 × 10-4- 5.6 × 10-4m3min-1m3interstitial water exchange (per mA).Significance. Using this pipeline, the fluid exchange rate per each brain voxel can be predicted for any tDCS dose (electrode montage, current) or anatomy. Under experimentally constrained tissue properties, we predicted tDCS produces a fluid exchange rate comparable to endogenous flow, so doubling fluid exchange with further local flow rate hot spots ('jets'). The validation and implication of such tDCS brain 'flushing' is important to establish.

Quasi-static pipeline in electroconvulsive therapy computational modeling.

BACKGROUND: Computational models of current flow during Electroconvulsive Therapy (ECT) rely on the quasi-static assumption, yet tissue impedance during ECT may be frequency specific and change adaptively to local electric field intensity. OBJECTIVES: We systematically consider the application of the quasi-static pipeline to ECT under conditions where 1) static impedance is measured before ECT and 2) during ECT when dynamic impedance is measured. We propose an update to ECT modeling accounting for frequency-dependent impedance. METHODS: The frequency content on an ECT device output is analyzed. The ECT electrode-body impedance under low-current conditions is measured with an impedance analyzer. A framework for ECT modeling under quasi-static conditions based on a single device-specific frequency (e.g., 1 kHz) is proposed. RESULTS: Impedance using ECT electrodes under low-current is frequency dependent and subject specific, and can be approximated at >100 Hz with a subject-specific lumped parameter circuit model but at <100 Hz increased non-linearly. The ECT device uses a 2 µA 800 Hz test signal and reports a static impedance that approximate 1 kHz impedance. Combined with prior evidence suggesting that conductivity does not vary significantly across ECT output frequencies at high-currents (800-900 mA), we update the adaptive pipeline for ECT modeling centered at 1 kHz frequency. Based on individual MRI and adaptive skin properties, models match static impedance (at 2 µA) and dynamic impedance (at 900 mA) of four ECT subjects. CONCLUSIONS: By considering ECT modeling at a single representative frequency, ECT adaptive and non-adaptive modeling can be rationalized under a quasi-static pipeline.

Spatiotemporal dynamics of brain activity during the transition from visually guided to memory-guided force control.

It is well established that the prefrontal cortex is involved during memory-guided tasks whereas visually guided tasks are controlled in part by a frontal-parietal network. However, the nature of the transition from visually guided to memory-guided force control is not as well established. As such, this study examines the spatiotemporal pattern of brain activity that occurs during the transition from visually guided to memory-guided force control. We measured 128-channel scalp electroencephalography (EEG) in healthy individuals while they performed a grip force task. After visual feedback was removed, the first significant change in event-related activity occurred in the left central region by 300 ms, followed by changes in prefrontal cortex by 400 ms. Low-resolution electromagnetic tomography (LORETA) was used to localize the strongest activity to the left ventral premotor cortex and ventral prefrontal cortex. A second experiment altered visual feedback gain but did not require memory. In contrast to memory-guided force control, altering visual feedback gain did not lead to early changes in the left central and midline prefrontal regions. Decreasing the spatial amplitude of visual feedback did lead to changes in the midline central region by 300 ms, followed by changes in occipital activity by 400 ms. The findings show that subjects rely on sensorimotor memory processes involving left ventral premotor cortex and ventral prefrontal cortex after the immediate transition from visually guided to memory-guided force control.

Study in Parkinson's disease of exercise phase 3 (SPARX3): study protocol for a randomized controlled trial.

BACKGROUND: To date, no medication has slowed the progression of Parkinson's disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline. METHODS: This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60-65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80-85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity. DISCUSSION: SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health. TRIAL REGISTRATION: ClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.

EMG responses to unexpected perturbations are delayed in slower movements.

It has previously been found that in fast point-to-point arm movements, proprioceptive feedback is centrally suppressed at the beginning of movement and is facilitated at a time that is correlated with temporal parameters of the planned movement. Here, we show that this correlation holds when subjects are explicitly instructed to move at less than maximal speed. We studied elbow flexion movements made at maximal speed and at 70% of maximal speed over a short distance against a light inertial load and over a long distance against a heavy inertial load. A small number of trials were unexpectedly perturbed by using a servo-controlled motor to decrease the movement velocity. The servo control was turned on early in the movement. The main novel finding is that responses in the surface EMG in the elbow muscles to the perturbation occurred later in the slow-speed conditions than fast-speed conditions. When viewed across all conditions, the onset of the EMG responses to the perturbation increased with the time to peak acceleration in unperturbed movements. In the inertial loaded movements, the time of peak acceleration coincides with the time of peak inertial torque, and so the observed correlation can be interpreted as reflecting the relation between either the planned movement kinematics or the planned movement dynamics. These results are compatible with a hypothesis that a descending command suppresses the proprioceptive feedback control at the movement onset and facilitates it at a time that depends on the time parameters of the planned movement.

Proprioceptive feedback during point-to-point arm movements is tuned to the expected dynamics of the task.

It has previously been found that in point-to-point movements against inertial loads, proprioceptive feedback is centrally suppressed in the beginning of movement and is facilitated at a time that is correlated with the expected time of peak velocity. This suggests that the modulation of proprioceptive feedback is governed by the desired movement kinematics. Here we show that in movements against inertial and viscous loads, the correlation of the time when the feedback is facilitated is strongest with the time when the joint torque is expected to be maximal. This suggests that the modulation of proprioceptive feedback is governed by the desired movement dynamics. We applied unexpected perturbations in point-to-point elbow flexion movements against known light and heavy inertial and viscous loads and determined the time and magnitude of responses in the electromyogram (EMG) of the biceps and triceps muscles. In movements against the inertial and viscous loads, the time of the EMG responses was better predicted by the time of the peak joint torque in the unperturbed movement than by the time of peak velocity or the time of peak acceleration or by measures related to the agonist EMG. Moreover, the EMG response changed from a reciprocal pattern in the inertial load conditions to a co-contraction pattern in the viscous load conditions. Our results suggest that during movements against known stable dynamic loads, proprioceptive feedback is tuned to the expected task dynamics and is facilitated so as to maintain muscle stiffness at a time when the muscles are expected to generate maximal force.

Wearable sensors for Parkinson's disease: which data are worth collecting for training symptom detection models.

Machine learning algorithms that use data streams captured from soft wearable sensors have the potential to automatically detect PD symptoms and inform clinicians about the progression of disease. However, these algorithms must be trained with annotated data from clinical experts who can recognize symptoms, and collecting such data are costly. Understanding how many sensors and how much labeled data are required is key to successfully deploying these models outside of the clinic. Here we recorded movement data using 6 flexible wearable sensors in 20 individuals with PD over the course of multiple clinical assessments conducted on 1 day and repeated 2 weeks later. Participants performed 13 common tasks, such as walking or typing, and a clinician rated the severity of symptoms (bradykinesia and tremor). We then trained convolutional neural networks and statistical ensembles to detect whether a segment of movement showed signs of bradykinesia or tremor based on data from tasks performed by other individuals. Our results show that a single wearable sensor on the back of the hand is sufficient for detecting bradykinesia and tremor in the upper extremities, whereas using sensors on both sides does not improve performance. Increasing the amount of training data by adding other individuals can lead to improved performance, but repeating assessments with the same individuals-even at different medication states-does not substantially improve detection across days. Our results suggest that PD symptoms can be detected during a variety of activities and are best modeled by a dataset incorporating many individuals.

Effect of High-Intensity Treadmill Exercise on Motor Symptoms in Patients With De Novo Parkinson Disease: A Phase 2 Randomized Clinical Trial.

Importance: Parkinson disease is a progressive neurologic disorder. Limited evidence suggests endurance exercise modifies disease severity, particularly high-intensity exercise. Objectives: To examine the feasibility and safety of high-intensity treadmill exercise in patients with de novo Parkinson disease who are not taking medication and whether the effect on motor symptoms warrants a phase 3 trial. Design, Setting, and Participants: The Study in Parkinson Disease of Exercise (SPARX) was a phase 2, multicenter randomized clinical trial with 3 groups and masked assessors. Individuals from outpatient and community-based clinics were enrolled from May 1, 2012, through November 30, 2015, with the primary end point at 6 months. Individuals with idiopathic Parkinson disease (Hoehn and Yahr stages 1 or 2) aged 40 to 80 years within 5 years of diagnosis who were not exercising at moderate intensity greater than 3 times per week and not expected to need dopaminergic medication within 6 months participated in this study. A total of 384 volunteers were screened by telephone; 128 were randomly assigned to 1 of 3 groups (high-intensity exercise, moderate-intensity exercise, or control). Interventions: High-intensity treadmill exercise (4 days per week, 80%-85% maximum heart rate [n = 43]), moderate-intensity treadmill exercise (4 days per week, 60%-65% maximum heart rate [n = 45]), or wait-list control (n = 40) for 6 months. Main Outcomes and Measures: Feasibility measures were adherence to prescribed heart rate and exercise frequency of 3 days per week and safety. The clinical outcome was 6-month change in Unified Parkinson's Disease Rating Scale motor score. Results: A total of 128 patients were included in the study (mean [SD] age, 64 [9] years; age range, 40-80 years; 73 [57.0%] male; and 108 [84.4%] non-Hispanic white). Exercise rates were 2.8 (95% CI, 2.4-3.2) days per week at 80.2% (95% CI, 78.8%-81.7%) maximum heart rate in the high-intensity group and 3.2 (95% CI, 2.8-3.6; P = .13) days per week at 65.9% (95% CI, 64.2%-67.7%) maximum heart rate in the moderate-intensity group (P < .001). The mean change in Unified Parkinson's Disease Rating Scale motor score in the high-intensity group was 0.3 (95% CI, -1.7 to 2.3) compared with 3.2 (95% CI, 1.4 to 5.1) in the usual care group (P = .03). The high-intensity group, but not the moderate-intensity group, reached the predefined nonfutility threshold compared with the control group. Anticipated adverse musculoskeletal events were not severe. Conclusions and Relevance: High-intensity treadmill exercise may be feasible and prescribed safely for patients with Parkinson disease. An efficacy trial is warranted to determine whether high-intensity treadmill exercise produces meaningful clinical benefits in de novo Parkinson disease. Trial Registration: clinicaltrials.gov Identifier: NCT01506479.

Two-year exercise program improves physical function in Parkinson's disease: the PRET-PD randomized clinical trial.

Background. The progressive resistance exercise (PRE) in Parkinson's disease trial (PRET-PD) showed that PRE improved the motor signs of PD compared to a modified Fitness Counts (mFC) program. It is unclear how long-term exercise affects physical function in these individuals. Objective. To examine the effects of long-term PRE and mFC on physical function outcome measures in individuals with PD. Methods. A preplanned secondary analysis was conducted using data from the 38 patients with idiopathic PD who completed the PRET-PD trial. Participants were randomized into PRE or mFC groups and exercised 2 days/week up to 24 months. Blinded assessors obtained functional outcomes on and off medication at baseline, 6 and 24 months with the Modified Physical Performance Test, 5 times sit to stand test, Functional Reach Test, Timed Up and Go, Berg Balance Scale, 6 minute walk test (6MWT), and 50-ft walking speed (walk speed). Results. The groups did not differ on any physical function measure at 6 or 24 months (Ps > .1). Across time, all physical function measures improved from baseline to 24 months when tested on medication (Ps < .0001), except for 6MWT (P = .068). Off medication results were similar except that the 6MWT was now significant. Conclusions. Twenty-four months of supervised and structured exercise (either PRE or mFC) is effective at improving functional performance outcomes in individuals with moderate PD. Clinicians should strive to include structured and supervised exercise in the long-term plan of care for individuals with PD.

Combined measures of movement and force variability distinguish Parkinson's disease from essential tremor.

OBJECTIVE: To examine whether behavioral and electrophysiological measures of motor performance accurately differentiate Parkinson's disease (PD) and essential tremor (ET). METHODS: Twenty-four patients (12 PD; 12 ET) performed isometric force, ballistic movements, and tremor tasks. Receiver operating characteristic (ROC) analyses were conducted on all dependent measures that were significantly different between the two patient groups. RESULTS: Patients with PD were more impaired on measures of movement deceleration than ET. Patients with ET were more impaired on measures of force variability than PD. ROC analyses revealed that sensitivity and specificity were excellent when combining measures during the isometric force task (torque rise time and force variability; 92% sensitivity and 92% specificity; AUC = 0.97). When combining measures across the force and movement tasks, the ROC analysis revealed improved sensitivity and specificity (force variability and peak deceleration; 92% sensitivity and 100% specificity; AUC = 0.99). CONCLUSIONS: Combining measures of force variability and movement deceleration accurately differentiate patients with PD from those with ET with high sensitivity and specificity. SIGNIFICANCE: If validated in a larger sample, these measures can serve as markers to confirm the diagnosis of PD or ET and thus, enhance decision making for appropriate treatments for patients with these respective diseases.