New directions in clinical trials for frontotemporal lobar degeneration: Methods and outcome measures.

INTRODUCTION: Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed. METHODS: In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD. RESULTS: Challenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges. DISCUSSION: New personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors.

Differential effects of deep brain stimulation target on motor subtypes in Parkinson's disease.

OBJECTIVE: The Veterans Administration Cooperative Studies Program #468, a multicenter study that randomized Parkinson's disease (PD) patients to either subthalamic nucleus (STN) or globus pallidus internus (GPi) deep brain stimulation (DBS), found that stimulation at either target provided similar overall motoric benefits. We conducted an additional analysis of this data set to evaluate whether PD motor subtypes responded differently to the 2 stimulation targets. METHODS: We classified 235 subjects by motor subtype: tremor dominant (TD), intermediate (I), or postural instability gait difficulty (PIGD), based on pre-DBS baseline Unified Parkinson's Disease Rating Scale (UPDRS) scores off-medication. The primary outcome was change in UPDRS part III (UPDRS-III) off-medication scores from baseline to 24 months post-DBS, compared among subjects with particular PD motor subtypes and by DBS target (STN vs GPi). Changes in tremor, rigidity, akinesia, and gait scores were also assessed using the UPDRS. RESULTS: TD patients had greater mean overall motor improvement, measured by UPDRS-III, after GPi DBS, compared to STN DBS (17.5 ± 13.0 vs 14.6 ± 14.9, p = 0.02), with improvement in gait accounting for this difference. Regardless of stimulation target, PIGD subjects had lower mean overall improvement in UPDRS-III scores compared with I or TD subjects (8.7 ± 12.2 vs 21.7 ± 11.2 vs 16.3 ± 13.8, p = 0.001). INTERPRETATION: Our results suggest that responsiveness to both GPi and STN DBS is similar among different PD motor subtypes, although the TD motor subtype may have a greater response to GPi DBS with respect to gait. PIGD patients obtained less overall benefit from stimulation.

Pregnancy in a Series of Dystonia Patients Treated with Deep Brain Stimulation: Outcomes and Management Recommendations.

BACKGROUND: Medically refractory dystonia affects children and young adults, and deep brain stimulation (DBS) can allow some patients to regain functional independence. Women with dystonia treated with DBS may wish to conceive a child, but there is limited published information on pregnancy and DBS. OBJECTIVE: To describe a series of dystonia patients treated with DBS who later became pregnant and provide guidelines for women treated with DBS considering conception. METHODS: We reviewed all dystonia DBS cases implanted at the University of California, San Francisco, and University of Alabama at Birmingham from 1998 to 2015 and identified patients who became pregnant. Patient records were reviewed and structured interviews were conducted. RESULTS: Six dystonia patients were identified [1 currently pregnant and 7 live births (including 1 twin pair)]. Patients (n = 5) with pre- and postoperative BFMDRS (Burke-Fahn-Marsden Dystonia Rating Scale) scores improved by 65.9% after DBS. All pregnancies and deliveries were uncomplicated (the delivery mode was not influenced by the presence of DBS), except for 1 child, who was born premature at 35 weeks' gestation. Stimulation remained on (n = 3) or off (n = 4) during deliveries. DBS neurostimulators did not hinder breastfeeding. CONCLUSIONS: In this small sample, pregnancy, delivery, and breastfeeding were safe in dystonia patients treated with DBS. The presence of DBS should not be a contraindication to pregnancy.

Cost-Effectiveness of Deep Brain Stimulation for Advanced Parkinson's Disease in the United States.

OBJECTIVES: Deep brain stimulation (DBS), which uses an implantable device to modulate brain activity, is clinically superior to medical therapy for treating advanced Parkinson's disease (PD). We studied the cost-effectiveness of DBS in conjunction with medical therapy compared to best medical therapy (BMT) alone, using the latest clinical and cost data for the U.S. healthcare system. MATERIALS AND METHODS: We used a decision-analytic state-transition (Markov) model to project PD progression and associated costs for the two treatment strategies. We estimated the discounted incremental cost-effectiveness ratio (ICER) in U.S. dollars per quality-adjusted life-year (QALY) from the Medicare payer perspective, considering a ten-year horizon, and evaluated the robustness of our projections through extensive deterministic sensitivity analyses. RESULTS: Over ten years, DBS treatment led to discounted total costs of $130,510 compared to $91,026 for BMT and added 1.69 QALYs more than BMT, resulting in an ICER of $23,404 per QALY. This ICER was relatively insensitive to variations in input parameters, with neurostimulator replacement, costs for DBS implantation, and costs for treatment of disease-related falls having the greatest effects. Across all investigated scenarios, including a five-year horizon, ICERs remained under $50,000 per QALY. Longer follow-up periods and younger treatment age were associated with greater cost-effectiveness. CONCLUSIONS: DBS is a cost-effective treatment strategy for advanced PD in the U.S. healthcare system across a wide range of assumptions. DBS yields substantial improvements in health-related quality of life at a value profile that compares favorably to other well-accepted therapies.

Neuropsychological changes following deep brain stimulation surgery for Parkinson's disease: comparisons of treatment at pallidal and subthalamic targets versus best medical therapy.

BACKGROUND: Deep brain stimulation (DBS) improves motor symptoms in Parkinson's disease (PD), but questions remain regarding neuropsychological decrements sometimes associated with this treatment, including rates of statistically and clinically meaningful change, and whether there are differences in outcome related to surgical target. METHODS: Neuropsychological functioning was assessed in patients with Parkinson's disease (PD) at baseline and after 6 months in a prospective, randomised, controlled study comparing best medical therapy (BMT, n=116) and bilateral deep brain stimulation (DBS, n=164) at either the subthalamic nucleus (STN, n=84) or globus pallidus interna (GPi, n=80), using standardised neuropsychological tests. Measures of functional outcomes were also administered. RESULTS: Comparison of the two DBS targets revealed few significant group differences. STN DBS was associated with greater mean reductions on some measures of processing speed, only one of which was statistically significant in comparison with stimulation of GPi. GPi DBS was associated with lower mean performance on one measure of learning and memory that requires mental control and cognitive flexibility. Compared to the group receiving BMT, the combined DBS group had significantly greater mean reductions at 6-month follow-up in performance on multiple measures of processing speed and working memory. After calculating thresholds for statistically reliable change from data obtained from the BMT group, the combined DBS group also displayed higher rates of decline in neuropsychological test performance. Among study completers, 18 (11%) study participants receiving DBS displayed reliable decline by multiple indicators in two or more cognitive domains, a significantly higher rate than in the BMT group (3%). This multi-domain cognitive decline was associated with less beneficial change in subjective ratings of everyday functioning and quality of life (QOL). The multi-domain cognitive decline group continued to function at a lower level at 24-month follow-up. CONCLUSIONS: In those with PD, the likelihood of significant decline in neuropsychological functioning increases with DBS, affecting a small minority of patients who also appear to respond less optimally to DBS by other indicators of QOL. TRIAL REGISTRATION NUMBER: NCT00056563 and NCT01076452.

Combining cell transplants or gene therapy with deep brain stimulation for Parkinson's disease.

Cell transplantation and gene therapy each show promise to enhance the treatment of Parkinson's disease (PD). However, because cell transplantation and gene therapy generally require direct delivery to the central nervous system, clinical trial design involves unique scientific, ethical, and financial concerns related to the invasive nature of the procedure. Typically, such biologics have been tested in PD patients who have not received any neurosurgical intervention. Here, we suggest that PD patients undergoing deep brain stimulation (DBS) device implantation are an ideal patient population for the clinical evaluation of cell transplantation and gene therapy. Randomizing subjects to an experimental group that receives the biologic concurrently with the DBS implantation-or to a control group that receives the DBS treatment alone-has several compelling advantages. First, this study design enables the participation of patients likely to benefit from DBS, many of whom simultaneously meet the inclusion criteria of biologic studies. Second, the need for a sham neurosurgical procedure is eliminated, which may reduce ethical concerns, promote patient recruitment, and enhance the blinding of surgical trials. Third, testing the biologic by "piggybacking" onto an established, reimbursable procedure should reduce the cost of clinical trials, which may allow a greater number of biologics to reach this critical stage of research translation. Finally, this clinical trial design may lead to combinatorial treatment strategies that provide PD patients with more durable control over disabling motor symptoms. By combining neuromodulation with biologics, we may also reveal important treatment paradigms relevant to other diseases of the brain.

Measuring Physical Functioning Using Wearable Sensors in Parkinson Disease and Chronic Obstructive Pulmonary Disease (the Accuracy of Digital Assessment of Performance Trial Study): Protocol for a Prospective Observational Study.

BACKGROUND: Physical capacity and physical activity are important aspects of physical functioning and quality of life in people with a chronic disease such as Parkinson disease (PD) or chronic obstructive pulmonary disease (COPD). Both physical capacity and physical activity are currently measured in the clinic using standardized questionnaires and tests, such as the 6-minute walk test (6MWT) and the Timed Up and Go test (TUG). However, relying only on in-clinic tests is suboptimal since they offer limited information on how a person functions in daily life and how functioning fluctuates throughout the day. Wearable sensor technology may offer a solution that enables us to better understand true physical functioning in daily life. OBJECTIVE: We aim to study whether device-assisted versions of 6MWT and TUG, such that the tests can be performed independently at home using a smartwatch, is a valid and reliable way to measure the performance compared to a supervised, in-clinic test. METHODS: This is a decentralized, prospective, observational study including 100 people with PD and 100 with COPD. The inclusion criteria are broad: age ≥18 years, able to walk independently, and no co-occurrence of PD and COPD. Participants are followed for 15 weeks with 4 in-clinic visits, once every 5 weeks. Outcomes include several walking tests, cognitive tests, and disease-specific questionnaires accompanied by data collection using wearable devices (the Verily Study Watch and Modus StepWatch). Additionally, during the last 10 weeks of this study, participants will follow an aerobic exercise training program aiming to increase physical capacity, creating the opportunity to study the responsiveness of the remote 6MWT. RESULTS: In total, 89 people with PD and 65 people with COPD were included in this study. Data analysis will start in April 2024. CONCLUSIONS: The results of this study will provide information on the measurement properties of the device-assisted 6MWT and TUG in the clinic and at home. When reliable and valid, this can contribute to a better understanding of a person's physical capacity in real life, which makes it possible to personalize treatment options. TRIAL REGISTRATION: ClinicalTrials.gov NCT05756075; https://clinicaltrials.gov/study/NCT05756075. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55452.

Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease.

BACKGROUND: Deep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinson's disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation). METHODS: At seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinson's disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events. RESULTS: Mean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months. CONCLUSIONS: Patients with Parkinson's disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)

Wrist-worn sensor-based measurements for drug effect detection with small samples in people with Lewy Body Dementia.

INTRODUCTION: Few late-stage clinical trials in Parkinson's disease (PD) have produced evidence on the clinical validity of sensor-based digital measurements of daily life activities to detect responses to treatment. The objective of this study was to assess whether digital measures from patients with mild-to-moderate Lewy Body Dementia demonstrate treatment effects during a randomized Phase 2 trial. METHODS: Substudy within a 12-week trial of mevidalen (placebo vs 10, 30, or 75 mg), where 70/344 patients (comparable to the overall population) wore a wrist-worn multi-sensor device. RESULTS: Treatment effects were statistically significant by conventional clinical assessments (Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS] sum of Parts I-III and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change [ADCS-CGIC] scores) in the full study cohort at Week 12, but not in the substudy. However, digital measurements detected significant effects in the substudy cohort at week 6, persisting to week 12. CONCLUSIONS: Digital measurements detected treatment effects in a smaller cohort over a shorter period than conventional clinical assessments. TRIAL REGISTRATION: clinicaltrials.gov, NCT03305809.

Analytical and clinical validity of wearable, multi-sensor technology for assessment of motor function in patients with Parkinson's disease in Japan.

Continuous, objective monitoring of motor signs and symptoms may help improve tracking of disease progression and treatment response in Parkinson's disease (PD). This study assessed the analytical and clinical validity of multi-sensor smartwatch measurements in hospitalized and home-based settings (96 patients with PD; mean wear time 19 h/day) using a twice-daily virtual motor examination (VME) at times representing medication OFF/ON states. Digital measurement performance was better during inpatient clinical assessments for composite V-scores than single-sensor-derived features for bradykinesia (Spearman |r|= 0.63, reliability = 0.72), tremor (|r|= 0.41, reliability = 0.65), and overall motor features (|r|= 0.70, reliability = 0.67). Composite levodopa effect sizes during hospitalization were 0.51-1.44 for clinical assessments and 0.56-1.37 for VMEs. Reliability of digital measurements during home-based VMEs was 0.62-0.80 for scores derived from weekly averages and 0.24-0.66 for daily measurements. These results show that unsupervised digital measurements of motor features with wrist-worn sensors are sensitive to medication state and are reliable in naturalistic settings.Trial Registration: Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC-CTI): JapicCTI-194825; Registered June 25, 2019.

Regional alterations of brain microstructure in Parkinson's disease using diffusion tensor imaging.

This study tested the hypothesis that diffusion tensor imaging can detect alteration in microscopic integrity of white matter and basal ganglia regions known to be involved in Parkinson's disease (PD) pathology. It was also hypothesized that there is an association between diffusion abnormality and PD severity and subtype. Diffusion tensor imaging at 4 Tesla was obtained in 12 PD and 20 control subjects, and measures of fractional anisotropy and mean diffusivity were evaluated using both region-of-interest and voxel-based methods. Movement deficits and subtypes in PD subjects were assessed using the Motor Subscale (Part III) of the Unified Parkinson's Disease Rating Scale. Reduced fractional anisotropy (P < .05, corrected) was found in PD subjects in regions related to the precentral gyrus, substantia nigra, putamen, posterior striatum, frontal lobe, and the supplementary motor areas. Reduced fractional anisotropy in the substantia nigra correlated (P < .05, corrected) with the increased rating scale motor scores. Significant spatial correlations between fractional anisotropy alterations in the putamen and other PD-affected regions were also found in the context of PD subtypes index analysis. Our data suggest that microstructural alterations detected with diffusion tensor might serve as a potential biomarker for PD.

Development of Parkinson's disease in patients with Narcolepsy.

Although amphetamine drugs can damage dopaminergic axons, it is unknown whether chronic treatment with amphetamine increases the risk of developing Parkinson's disease (PD). Of 1,152 consecutive PD patients, 3 had a prior diagnosis of narcolepsy. This rate is five times higher than expected (p = 0.02). These patients had typical onset of narcolepsy and underwent treatment with amphetamine. Although preliminary, this observation raises the possibility that some factors intrinsic to narcolepsy or its treatment may be a risk factor for PD.

Virtual exam for Parkinson's disease enables frequent and reliable remote measurements of motor function.

Sensor-based remote monitoring could help better track Parkinson's disease (PD) progression, and measure patients' response to putative disease-modifying therapeutic interventions. To be useful, the remotely-collected measurements should be valid, reliable, and sensitive to change, and people with PD must engage with the technology. We developed a smartwatch-based active assessment that enables unsupervised measurement of motor signs of PD. Participants with early-stage PD (N = 388, 64% men, average age 63) wore a smartwatch for a median of 390 days. Participants performed unsupervised motor tasks both in-clinic (once) and remotely (twice weekly for one year). Dropout rate was 5.4%. Median wear-time was 21.1 h/day, and 59% of per-protocol remote assessments were completed. Analytical validation was established for in-clinic measurements, which showed moderate-to-strong correlations with consensus MDS-UPDRS Part III ratings for rest tremor (⍴ = 0.70), bradykinesia (⍴ = -0.62), and gait (⍴ = -0.46). Test-retest reliability of remote measurements, aggregated monthly, was good-to-excellent (ICC = 0.75-0.96). Remote measurements were sensitive to the known effects of dopaminergic medication (on vs off Cohen's d = 0.19-0.54). Of note, in-clinic assessments often did not reflect the patients' typical status at home. This demonstrates the feasibility of smartwatch-based unsupervised active tests, and establishes the analytical validity of associated digital measurements. Weekly measurements provide a real-life distribution of disease severity, as it fluctuates longitudinally. Sensitivity to medication-induced change and improved reliability imply that these methods could help reduce sample sizes needed to demonstrate a response to therapeutic interventions or disease progression.

Predictors of multi-domain cognitive decline following DBS for treatment of Parkinson's disease.

BACKGROUND: Statistically and clinically significant cognitive declines are observed in a small subset of individuals with Parkinson's Disease (PD) following treatment with Deep Brain Stimulation (DBS). OBJECTIVES: We examine the association between multi-domain cognitive decline (MCD) and demographic and baseline clinical variables and the incidence of serious adverse events (SAE) arising within a six-month interval following DBS for PD. METHOD: Study participants with PD who displayed MCD at 6-month follow-up evaluation after DBS (n = 18) were contrasted with individuals with PD from the same study who did not show cognitive decline after DBS (n = 146). Logistic regression analyses were employed to assess relationship between predictors, including age (>70 years old), pre-DBS cognitive screening test performance, SAE, and MCD. MCD+ and MCD-groups were also compared on other baseline clinical and demographic variables. RESULTS: MCD showed modest association with older age and lower baseline neurocognitive screening performance, whereas the groups did not differ on most other baseline clinical and demographic variables. SAEs during the study interval were the most robust predictor of MCD in the DBS group. A variety of SAEs were documented in study participants experiencing MCD after DBS surgery, including, but not limited to, infections and small intracranial hemorrhages. CONCLUSIONS: Older age and lower baseline cognition measured prior to treatment are associated with MCD measured at six-months after DBS. SAE occurring following DBS surgery are also predictive of MCD. These predictors may reflect aspects of "frailty" in advanced PD. Risk factors for SAE warrant careful consideration in clinical trials.

Inclusion and exclusion criteria for DBS in dystonia.

When considering a patient with dystonia for deep brain stimulation (DBS) surgery several factors need to be considered. Level B evidence has shown that all motor features and associated pain in primary generalized and segmental dystonia are potentially responsive to globus pallidus internus (GPi) DBS. However, improvements in clinical series of ≥ 90% may reflect methods that need improvement, and larger prospective studies are needed to address these factors. Nevertheless, to date the selection criteria for DBS-specifically in terms of patient features (severity and nature of symptoms, age, time of evolution, or any other demographic or disease aspects)--have not been assessed in a systematic fashion. In general, dystonia patients are not considered for DBS unless medical therapies have been previously and extensively tested. The vast majority of reported patients have had DBS surgery when the disease was provoking important disability, with loss of independence and impaired quality of life. There does not appear to be an upper age limit or a minimum age limit, although there are no published data regarding the outcome of GPi DBS for dystonia in children younger than 7 years of age. There is currently no enough evidence to prove that subjects with primary--generalized dystonia who undergo DBS at an early age and sooner rather than later after disease onset may gain more benefit from DBS than those undergoing DBS after the development of fixed skeletal deformities. There is no enough evidence to refuse or support consideration of DBS in patients with previous ablative procedures.

An update on gene therapy in Parkinson's disease.

Gene therapy for Parkinson's disease (PD) may offer an alternative to current pharmacologic and surgical treatments; the former are limited by motor complications and non-motor adverse effects, and both by lack of neuroprotection. Three main strategies under investigation using gene transfer for targeted protein expression include improving availability of dopamine to the striatum with more continuous delivery, reducing activity in the subthalamic nucleus by locally inducing γ-aminobutyric acid expression, or protecting and restoring nigrostriatal neuronal function with trophic factor expression. This review summarizes the components of gene therapy for PD, the preclinical rationale for each strategy, data from the most recently published clinical trials using four different vector-gene agents, and challenges in moving gene therapy forward. Thus far, safety data from phase 1 trials have been encouraging for all four agents and one phase 2 trial suggests modest symptomatic efficacy, but definitive conclusions on efficacy cannot yet be drawn.

Toward a Mobile Platform for Real-world Digital Measurement of Depression: User-Centered Design, Data Quality, and Behavioral and Clinical Modeling.

BACKGROUND: Although effective mental health treatments exist, the ability to match individuals to optimal treatments is poor, and timely assessment of response is difficult. One reason for these challenges is the lack of objective measurement of psychiatric symptoms. Sensors and active tasks recorded by smartphones provide a low-burden, low-cost, and scalable way to capture real-world data from patients that could augment clinical decision-making and move the field of mental health closer to measurement-based care. OBJECTIVE: This study tests the feasibility of a fully remote study on individuals with self-reported depression using an Android-based smartphone app to collect subjective and objective measures associated with depression severity. The goals of this pilot study are to develop an engaging user interface for high task adherence through user-centered design; test the quality of collected data from passive sensors; start building clinically relevant behavioral measures (features) from passive sensors and active inputs; and preliminarily explore connections between these features and depression severity. METHODS: A total of 600 participants were asked to download the study app to join this fully remote, observational 12-week study. The app passively collected 20 sensor data streams (eg, ambient audio level, location, and inertial measurement units), and participants were asked to complete daily survey tasks, weekly voice diaries, and the clinically validated Patient Health Questionnaire (PHQ-9) self-survey. Pairwise correlations between derived behavioral features (eg, weekly minutes spent at home) and PHQ-9 were computed. Using these behavioral features, we also constructed an elastic net penalized multivariate logistic regression model predicting depressed versus nondepressed PHQ-9 scores (ie, dichotomized PHQ-9). RESULTS: A total of 415 individuals logged into the app. Over the course of the 12-week study, these participants completed 83.35% (4151/4980) of the PHQ-9s. Applying data sufficiency rules for minimally necessary daily and weekly data resulted in 3779 participant-weeks of data across 384 participants. Using a subset of 34 behavioral features, we found that 11 features showed a significant (P<.001 Benjamini-Hochberg adjusted) Spearman correlation with weekly PHQ-9, including voice diary-derived word sentiment and ambient audio levels. Restricting the data to those cases in which all 34 behavioral features were present, we had available 1013 participant-weeks from 186 participants. The logistic regression model predicting depression status resulted in a 10-fold cross-validated mean area under the curve of 0.656 (SD 0.079). CONCLUSIONS: This study finds a strong proof of concept for the use of a smartphone-based assessment of depression outcomes. Behavioral features derived from passive sensors and active tasks show promising correlations with a validated clinical measure of depression (PHQ-9). Future work is needed to increase scale that may permit the construction of more complex (eg, nonlinear) predictive models and better handle data missingness.

The Project Baseline Health Study: a step towards a broader mission to map human health.

The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.

Induction of bradykinesia with pallidal deep brain stimulation in patients with cranial-cervical dystonia.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective and well-tolerated treatment for idiopathic generalized dystonia. More recently, it has been applied as a treatment for focal and segmental dystonias. This patient population offers an opportunity to study the effects of alteration of pallidal outflow on previously normal limb function. METHODS: We sought to retrospectively characterize the extent of novel GPi DBS-induced adverse motor effects in patients with adult-onset cervical and cranial-cervical dystonia using a questionnaire, and compared the findings to dystonia improvement as measured by standard scales. RESULTS: Despite significant improvement in dystonia (65% in mean Burke-Fahn-MarsdenDystonia Rating Scale motor score, p < 0.005, and 59% in mean Toronto Western Spasmodic Torticollis Rating Scale score, p < 0.008), slowing and difficulty with normal motor function was reported in previously nondystonic extremities in 10 of 11 patients. Symptoms were common in both upper and lower extremities and included new difficulties with handwriting (82%), getting up from a chair or in/out of a car (73%), and walking (45%), and were not associated with aberrant lead placement near the internal capsule. CONCLUSION: Although GPi DBS was shown to be effective in these patients, the influence of GPi DBS on nondystonic body regions deserves further investigation.

Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial.

CONTEXT: Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients. OBJECTIVE: To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age (< 70 years vs > or = 70 years) at 7 Veterans Affairs and 6 university hospitals between May 2002 and October 2005. A total of 255 patients with PD (Hoehn and Yahr stage > or = 2 while not taking medications) were enrolled; 25% were aged 70 years or older. The final 6-month follow-up visit occurred in May 2006. INTERVENTION: Bilateral deep brain stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61). Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists. MAIN OUTCOME MEASURES: The primary outcome was time spent in the "on" state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events. RESULTS: Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P < .001). Motor function improved significantly (P < .001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements (> or = 5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (P < .001). Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P < .001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage. CONCLUSION: In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00056563.