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Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD.To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation.Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791).Outpatient.150 patients with PD and constipation.ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period.The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]).The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (Longer treatment periods need to be investigated in future studies.ENT-01 was safe and significantly improved constipation.Enterin, Inc.

OBJECTIVE To assess use of directional stimulation in Parkinson's disease and essential tremor patients programmed in routine clinical care. MATERIALS AND METHODS Patients with Parkinson's disease or essential tremor implanted at Cleveland Clinic with a directional deep brain stimulation (DBS) system from November 2017 to October 2019 were included in this retrospective case series. Omnidirectional was compared against directional stimulation using therapeutic current strength, therapeutic window percentage, and total electrical energy delivered as outcome variables. RESULTS Fifty-seven Parkinson's disease patients (36 males) were implanted in the subthalamic nucleus (105 leads) and 33 essential tremor patients (19 males) were implanted in the ventral intermediate nucleus of the thalamus (52 leads). Seventy-four percent of patients with subthalamic stimulation (65% of leads) and 79% of patients with thalamic stimulation (79% of leads) were programmed with directional stimulation for their stable settings. Forty-six percent of subthalamic leads and 69% of thalamic leads were programmed on single segment activation. There was no correlation between the length of microelectrode trajectory through the STN and use of directional stimulation. CONCLUSIONS Directional programming was more common than omnidirectional programming. Substantial gains in therapeutic current strength, therapeutic window, and total electrical energy were found in subthalamic and thalamic leads programmed on directional stimulation.

Background The initial COVID-19 pandemic shutdown led to the canceling of elective surgeries throughout most of the USA and Canada. Objective This survey was carried out on behalf of the Parkinson Study Group (PSG) to understand the impact of the shutdown on deep brain stimulation (DBS) practices in North America. Methods A survey was distributed through RedCap® to the members of the PSG Functional Neurosurgical Working Group. Only one member from each site was asked to respond to the survey. Responses were collected from May 15 to June 6, 2020. Results Twenty-three sites participated; 19 (83%) sites were from the USA and 4 (17%) from Canada. Twenty-one sites were academic medical centers. COVID-19 associated DBS restrictions were in place from 4 to 16 weeks. One-third of sites halted preoperative evaluations, while two-thirds of the sites offered limited preoperative evaluations. Institutional policy was the main contributor for the reported practice changes, with 87% of the sites additionally reporting patient-driven surgical delays secondary to pandemic concerns. Pre-post DBS associated management changes affected preoperative assessments 96%; electrode placement 87%; new implantable pulse generator (IPG) placement 83%; IPG replacement 65%; immediate postoperative DBS programming 74%; and routine DBS programming 91%. Conclusion The COVID-19 pandemic related shutdown resulted in DBS practice changes in almost all North American sites who responded to this large survey. Information learned could inform development of future contingency plans to reduce patient delays in care under similar circumstances.

Augmented reality (AR) may be a useful tool for the delivery of dual-task training. This manuscript details the development of the Dual-task Augmented Reality Treatment (DART) platform for individuals with Parkinson’s disease (PD) and reports initial feasibility, usability, and efficacy of the DART platform in provoking dual-task interference in individuals with PD. The DART platform utilizes the head-mounted Microsoft HoloLens2 AR device to deliver concurrent motor and cognitive tasks. Biomechanical metrics of gait and cognitive responses are automatically computed and provided to the supervising clinician. To assess feasibility, individuals with PD (N = 48) completed a bout of single-task and dual-task walking using the DART platform. Usability was assessed by the System Usability Scale (SUS). Dual-task interference was assessed by comparing single-task walking and walking during an obstacle course while performing a cognitive task. Average gait velocity decreased from 1.06 to 0.82 m/s from single- to dual-task conditions. Mean SUS scores were 81.3 (11.3), which placed the DART in the “good” to “excellent” category. To our knowledge, the DART platform is the first to use a head-mounted AR system to deliver a dual-task paradigm and simultaneously provide biomechanical data that characterize cognitive and motor performance. Individuals with PD were able to successfully use the DART platform with satisfaction, and dual-task interference was provoked. The DART platform should be investigated as a platform to treat dual-task declines associated with PD.

To assess and validate the Smart Exercise Bike designed for Parkinson's Disease (PD) rehabilitation, 47 individuals with PD were randomly assigned to either the static or dynamic cycling group, and completed three sessions of exercise. Heart rate, cadence and power data were captured and recorded for each patient during exercise. Motor function for each subject was assessed with the UPDRS Motor III test before and after the three exercise sessions to evaluate the effect of exercise on functional abilities. Individuals who completed three sessions of dynamic cycling showed an average of 13.8% improvement in the UPDRS, while individuals in the static cycling group worsened by 1.6% in UPDRS. To distinguish the static and dynamic cycling groups by biomechanical and physiological features, the complexity of the recorded signals (cadence, power, and heart rate) was examined using approximate entropy (ApEn), sample entropy (SaEn) and spectral entropy (SpEn) as measures of variability. A multiple linear regression (MLR) model was used to relate these features to changes in motor function as measured by the UPDRS Motor III scale. Pattern variability in cadence was greater in the dynamic group when compared to the static group. In contrast, variability in power was greater for the static group. UPDRS Motor III scores predicted from the pattern variability data were correlated to measured scores in both groups. These results support our previous study which explained how variability analysis results for biomechanical and physiological parameters of exercise can be used to predict improvements in motor function.

Objectives Exercise can improve motor function in people with Parkinson's disease but depression reduces the motivation to participate in regular exercise. The aim of this study was to develop a novel Enhanced Exercise Therapy program that uses manual-driven guided exercise and peer-facilitated psychoeducation for individuals with Parkinson's disease and depression. Design 24 week randomized controlled design. Methods Thirty individuals were randomized to Enhanced Exercise Therapy or self-guided therapy, and evaluated at baseline, 12-weeks and at 24-weeks. Enhanced Exercise Therapy included group exercise and group psychoeducation for 12 weeks. Between 13 and 24 weeks, individuals had access to the fitness facility but group sessions were not held. Self-guided therapy included written guidelines for a self-paced exercise program and psychoeducation. Primary outcome measures included the number of exercise sessions and International Physical Activity Questionnaire score. Secondary measures included resting heart rate, supine blood pressure, estimated VO2max and incidence of orthostatic hypotension. Results Twenty four individuals completed the study (80% retention) and both groups attended similar number of exercise sessions. There were no significant changes in cardiovascular fitness measures but there was a significant increase in the amount of physical activity in the Enhanced Exercise Therapy group and a decrease in the self-guided therapy group during the post-intervention period. Conclusions Enhanced Exercise Therapy appears to promote engagement in an exercise program and more physical activity, even after group sessions were concluded in individuals with Parkinson's disease and depression.

Object Stimulation of white matter pathways near targeted structures may contribute to therapeutic effects of deep brain stimulation (DBS) for patients with Parkinson disease (PD). Two tracts linking the basal ganglia and cerebellum have been described in primates: the subthalamopontocerebellar tract (SPCT) and the dentatothalamic tract (DTT). The authors used fiber tractography to evaluate white matter tracts that connect the cerebellum to the region of the basal ganglia in patients with PD who were candidates for DBS. Methods Fourteen patients with advanced PD underwent 3-T MRI, including 30-directional diffusion-weighted imaging sequences. Diffusion tensor tractography was performed using 2 regions of interest: ipsilateral subthalamic and red nuclei, and contralateral cerebellar hemisphere. Nine patients underwent subthalamic DBS, and the course of each tract was observed relative to the location of the most effective stimulation contact and the volume of tissue activated. Results In all patients 2 distinct tracts were identified that corresponded closely to the described anatomical features of the SPCT and DTT, respectively. The mean overall distance from the active contact to the DTT was 2.18 ± 0.35 mm, and the mean proportional distance relative to the volume of tissue activated was 1.35 ± 0.48. There was a nonsignificant trend toward better postoperative tremor control in patients with electrodes closer to the DTT. Conclusions The SPCT and the DTT may be related to the expression of symptoms in PD, and this may have implications for DBS targeting. The use of tractography to identify the DTT might assist with DBS targeting in the future.

Ablation or deep brain stimulation in the internal segment of the globus pallidus (GPi) is an effective therapy for the treatment of Parkinson's disease (PD). Yet many patients receive only partial benefit, including varying levels of improvement across different body regions, which may relate to a differential effect of GPi surgery on the different body regions. Unfortunately, our understanding of the somatotopic organization of human GPi is based on a small number of studies with limited sample sizes, including several based upon only a single recording track or plane. To fully address the three-dimensional somatotopic organization of GPi, we examined the receptive field properties of pallidal neurons in a large cohort of patients undergoing stereotactic surgery. The response of neurons to active and passive movements of the limbs and orofacial structures was determined, using a minimum of three tracks across at least two medial-lateral planes. Neurons (3183) were evaluated from 299 patients, of which 1972 (62%) were modulated by sensorimotor manipulation. Of these, 1767 responded to a single, contralateral body region, with the remaining 205 responding to multiple and/or ipsilateral body regions. Leg-related neurons were found dorsal, medial and anterior to arm-related neurons, while arm-related neurons were dorsal and lateral to orofacial-related neurons. This study provides a more detailed map of individual body regions as well as specific joints within each region and provides a potential explanation for the differential effect of lesions or DBS of the GPi on different body parts in patients undergoing surgical treatment of movement disorders.

Objective: Despite the clinical success of deep brain stimulation (DBS) for the treatment of Parkinson’s disease (PD), little is known about the electrical spread of the stimulation. The primary goal of this study was to integrate neuroimaging, neurophysiology and neurostimulation data sets from 10 patients with PD, unilaterally implanted with subthalamic nucleus (STN) DBS electrodes, to identify the theoretical volume of tissue activated (VTA) by clinically defined therapeutic stimulation parameters. Methods: Each patient specific model was created with a series of five steps: (1) definition of the neurosurgical stereotactic coordinate system within the context of preoperative imaging data; (2) entry of intraoperative microelectrode recording locations from neurophysiologically defined thalamic, subthalamic and substantia nigra neurons into the context of the imaging data; (3) fitting a three dimensional brain atlas to the neuroanatomy and neurophysiology of the patient; (4) positioning the DBS electrode in the documented stereotactic location, verified by postoperative imaging data; and (5) calculation of the VTA using a diffusion tensor based finite element neurostimulation model. Results: The patient specific models show that therapeutic benefit was achieved with direct stimulation of a wide range of anatomical structures in the subthalamic region. Interestingly, of the five patients exhibiting a greater than 40% improvement in their Unified PD Rating Scale (UPDRS), all but one had the majority of their VTA outside the atlas defined borders of the STN. Furthermore, of the five patients with less than 40% UPDRS improvement, all but one had the majority of their VTA inside the STN. Conclusions: Our results are consistent with previous studies suggesting that therapeutic benefit is associated with electrode contacts near the dorsal border of the STN, and provide quantitative estimates of the electrical spread of the stimulation in a clinically relevant context.

Background: Deep brain stimulation (DBS) of the subthalamic region is an established therapy for advanced Parkinson's disease (PD). However, patients often require time-intensive post-operative management to balance their coupled stimulation and medication treatments. Given the large and complex parameter space associated with this task, we propose that clinical decision support systems (CDSS) based on machine learning algorithms could assist in treatment optimization. Objective: Develop a proof-of-concept implementation of a CDSS that incorporates patient-specific details on both stimulation and medication. Methods: Clinical data from 10 patients, and 89 post-DBS surgery visits, were used to create a prototype CDSS. The system was designed to provide three key functions: 1) information retrieval; 2) visualization of treatment, and; 3) recommendation on expected effective stimulation and drug dosages, based on three machine learning methods that included support vector machines, Naïve Bayes, and random forest. Results: Measures of medication dosages, time factors, and symptom-specific pre-operative response to levodopa were significantly correlated with post-operative outcomes (P

Deep brain stimulation (DBS) is an established therapy for the management of advanced Parkinson's disease (PD). However, the coupled adjustment of pharmacologic therapy and stimulation parameter settings is a time-consuming process and treatment outcomes are not always optimal. In this study, we develop a linear function that relates the DBS parameters, the levodopa dosage, and patient-specific preoperative clinical data with the actual treatment motor outcomes. To this end, we incorporate image-based patient-specific computer models of the volume of tissue activated by DBS in a multilinear regression analysis (6 PD patients; 60 follow up visits). The resulting predictor function was highly correlated with the actual motor outcomes (r = 0.76; p0.05). These results demonstrate that the outcomes of a combined pharmacologic-DBS therapy can be predicted and may facilitate patient-specific treatment optimization for maximal benefits and minimal adverse effects.

BACKGROUND Microelectrode recording helps surgeons accurately localize boundaries of the subthalamic nucleus (STN) and surrounding structures in deep brain stimulation. OBJECTIVE To describe a novel adaptation of the Ben gun device to optimize efficient mapping. METHODS Patients who underwent STN deep brain stimulation over a 3-year period were reviewed. For the final year, the Ben gun was rotated 45° and the target was offset 1.4 mm lateral and anterior in the plane orthogonal to the intended trajectory to allow for simultaneous parallel tracks at target, 2.8 mm anterior (localizing the front of STN), and 2.8 mm lateral (identifying the internal capsule). Before this step, the initial pass consisted of 1 to 2 tracks with the frame center targeted to STN. The primary outcome measure was the number of passes required for accurate localization of the nucleus and boundaries. RESULTS Eighty-three electrodes were implanted in 45 patients (mean age, 62; range, 37-78 years), of which 29 electrodes were placed by the use of the new technique. One electrode (4%) required more than 1 pass using the new technique compared with 36 (67%) using the older technique (P < .01). The distance from original target to final electrode position increased from 0.67 ± 0.13 mm to 1.06 ± 0.15 mm (P < .05) with a greater tendency to move the final electrode position posteriorly. There was no statistically significant difference in benefit from neurostimulation. CONCLUSION This technique facilitates reliable localization of the STN with fewer passes, possibly decreasing the risks associated with more passes and longer duration of surgery.

We describe a case of pseudobulbar crying associated with deep brain stimulation (DBS) in the region of the subthalamic nucleus (STN). Patients with pseudobulbar crying show no other evidence of subjective feelings of depression such as dysphoria, anhedonia, or vegetative signs. This may be accompanied by other symptoms of pseudobulbar palsy and has been reported to occur with ischaemic or structural lesions in both cortical and subcortical regions of the brain. Although depression has been observed to result from DBS in the region of the STN, pseudobulbar crying has not been reported. A single patient who reported the symptoms of pseudobulbar crying after placement of an STN DBS was tested in the off DBS and on DBS conditions. The patient was tested using all four DBS lead contacts and the observations and results of the examiners were recorded. The Geriatric Depression Scale was used to evaluate for depression in all of the conditions. The patient exhibited pseudobulbar crying when on monopolar stimulation at all four lead contacts. The pseudobulbar crying resolved off stimulation. This case describes another type of affective change that may be associated with stimulation in the region of or within the STN. Clinicians should be aware of this potential complication, the importance of differentiating it from stimulation induced depression, and its response to a serotonin reuptake inhibitor, such as sertraline.

Gait and balance disturbances in Parkinson's disease (PD) can be debilitating and may lead to increased fall risk. Deep brain stimulation (DBS) is a treatment option once therapeutic benefits from medication are limited due to motor fluctuations and dyskinesia. Optimizing DBS parameters for gait and balance can be significantly more challenging than for other PD motor symptoms. Furthermore, inter-rater reliability of the standard clinical PD assessment scale, Unified Parkinson's Disease Rating Scale (UPDRS), may introduce bias and washout important features of gait and balance that may respond differently to PD therapies. Study objectives were to evaluate clinician UPDRS gait and balance scoring inter-rater reliability, UPDRS sensitivity to different aspects of gait and balance, and how kinematic features extracted from motion sensor data respond to stimulation. Forty-two subjects diagnosed with PD were recruited with varying degrees of gait and balance impairment. All subjects had been prescribed dopaminergic medication, and 20 subjects had previously undergone DBS surgery. Subjects performed seven items of the gait and balance subset of the UPDRS while wearing motion sensors on the sternum and each heel and thigh. Inter-rater reliability varied by UPDRS item. Correlation coefficients between at least one kinematic feature and corresponding UPDRS scores were greater than 0.75 for six of the seven items. Kinematic features improved (p0.05) from DBS-OFF to DBS-ON for three UPDRS items. Despite achieving high correlations with the UPDRS, evaluating individual kinematic features may help address inter-rater reliability issues and rater bias associated with focusing on different aspects of a motor task.

Depression has been estimated to affect 1 in 3 individuals with Parkinson's disease (PD) and can lead to worse health outcomes and decreased quality of life. Anxiety further complicates PD outcomes. Pharmacologic treatments of depression and anxiety can have negative side effects in patients with PD, including exacerbation of PD symptoms. There is a critical need for alternative treatment approaches that address depression and anxiety among patients with PD. Psychosocial or behavioral approaches are known to be effective for depression generally, but only a handful of studies have examined the role of psychosocial treatments of patients with depression in PD.The aim of this article was to review published psychosocial treatment studies of depression and anxiety in patients with PD.The PubMed database was searched for articles published in English before April 2011 using the terms Parkinson's disease, depression, anxiety, psychotherapy, cognitive therapy, behavioral treatment, behavioral therapy, nonpharmacologic treatment, psychoeducation, education, psychosocial treatment, and stress management. Articles included were prospective clinical trials utilizing specific depression or anxiety assessments as primary or secondary outcomes in patients with PD.Nine reports derived from 8 separate studies fit the inclusion criteria and were included in this review. All studies were published between 1997 and 2011, and all but 3 had small sample sizes (40 patients). Interventions included cognitive behavioral therapy (CBT), psychodrama, education, and behavior therapy as well as multidisciplinary rehabilitation. Cognitive behavioral therapy was the most studied and was shown to decrease depressive and anxiety symptoms in patients with PD. Other individual and group therapies may improve depression and anxiety in patients with PD, but the general paucity of studies and study methods limit the interpretation of these results.There have been few studies on psychosocial treatments that specifically assess change in depression and anxiety among patients with PD. While results for CBT and other modes of therapy are promising for acute management of depression and anxiety, longer term effects after treatment have been variable. There is a need for additional studies on psychosocial interventions in people with PD.

The objective was to develop and evaluate algorithms for quantifying gait and lower extremity bradykinesia in patients with Parkinson's disease using kinematic data recorded on a heel-worn motion sensor unit. Subjects were evaluated by three movement disorder neurologists on four domains taken from the Movement Disorders Society Unified Parkinson's Disease Rating Scale while wearing the motion sensor unit. Multiple linear regression models were developed based on the recorded kinematic data and clinician scores and produced outputs highly correlated to clinician scores with an average correlation coefficient of 0.86. The newly developed models have been integrated into a home-based system for monitoring Parkinson's disease motor symptoms.

Summary Since the early 1930s, physicians have developed and refined various surgical therapies for the treatment of Parkinson's disease. In this review we examine some of the problems associated with early surgical therapies, the development of new techniques and targets, and the results of clinical trials examining the safety and efficacy of these techniques. Ablative techniques include pallidotomy, thalamotomy, and, more recently, subthalamotomy. Because of concern over the high incidence of side-effects associated with bilateral ablative procedures, alternative approaches were explored. Deep brain stimulation (DBS) was subsequently developed and successfully applied in the internal globus pallidus, subthalamic nucleus, and thalamus for the treatment of Parkinson's disease. Recent approaches include biological neurorestorative techniques—surgical therapies with transplantation, gene therapy, and growth factors are all being studied. Although a great deal of work remains to be done, advances in surgical therapies for the treatment of Parkinson's disease are moving forward at an unprecedented pace.

Autonomic dysfunction is common in parkinsonian syndromes, particularly those involving dysregulation of alpha-synuclein, and may result from neurodegeneration in autonomic regulatory regions of the brain or peripherial autonomic ganglia. The most limiting cardiovascular autonomic dysfunction in these diseases is orthostatic hypotension, which is particularly prominent in multiple system atrophy. Postprandial hypotension and supine hypertension, as well as dopaminergic therapy, often complicate the management of orthostatic hypotension in patients with parkinsonian syndromes.

Objective: To investigate whether a single daily dose of testosterone replacement gel has beneficial effects on testosterone deficiency symptoms, cognitive function, nonmotor symptoms of Parkinson disease (PD), and motor symptoms of PD. Background: Recently it has been observed that testosterone replacement therapy improves refractory nonmotor symptoms in testosterone-deficient men with PD. Many of the symptoms of testosterone deficiency are nonspecific and overlap with the nonmotor symptoms of PD, such as decreased enjoyment of life, lack of energy, sexual dysfunction, and depression. Replacement therapy for men with PD and comorbid testosterone deficiency may be an important addition to antiparkinsonian management strategies. Methods: A prospective open-labeled pilot study of testosterone topical gel (5 g of AndroGel; Unimed Pharmaceutical Inc, Deerfield, Ill) administered daily to testosterone-deficient (free testosterone80 pg/mL) men with PD. All 10 patients were followed up for 1 month and 6 patients were followed up for a total of 3 months. Patients were administered a battery of testosterone deficiency questionnaires, cognitive studies, and scales of PD nonmotor and motor function at baseline, 1, and 3 months. Results: With the daily transdermal testosterone gel, patients had an average increase in levels of free testosterone from baseline (53 pg/mL) to a 1-month follow-up visit (131 pg/mL; P=.06) and to a 3-month follow-up visit (98 pg/mL; P=.04). Testosterone deficiency symptoms improved in these patients (St Louis Testosterone Deficiency Questionnaire) from baseline (7.9 deficiency symptoms) to 1 month (5.6 deficiency symptoms, P=.04) and 3 months (5.8 deficiency symptoms, P=.08). The Unified Parkinson’s Disease Rating Scale IV showed improvement at 1 month (P=.008). Additionally, there were trends toward improvement in the following scales: Unified Parkinson’s Disease Rating Scale I at the 3-month follow-up (P = .09), Letter Fluency at the 3-month follow-up (P=.08), and the Hamilton Anxiety Scale at the 1-month follow-up (P=.09). Conclusions: A daily dose of transdermal testosterone gel improved testosterone deficiency symptoms in men with PD. Although there were trends in improvement in other nonmotor and motor symptoms of PD, future placebo control studies will need to be powered to answer these important questions. Whether testosterone deficiency is simply a comorbidity in PD or whether it plays a role in the pathogenesis of disease also remains for future study. Arch Neurol. 2002;59:1750-1753