IMPORTANCEParkinson 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 PARTICIPANTSThe 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.

An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback-guided control of brain activation, i.e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first- (single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate cortex, the dorsolateral and ventrolateral prefrontal cortex, the temporo-parietal area and the visual association areas including the temporo-occipital junction. In conclusion, we demonstrate that several key regions, such as the anterior insula and the basal ganglia, are consistently activated during self-regulation in real-time fMRI neurofeedback independent of the targeted region-of-interest. Our results imply that if the real-time fMRI neurofeedback studies target regions of this regulation network, such as the anterior insula, care should be given whether activation changes are related to successful regulation, or related to the regulation process per se. Furthermore, future research is needed to determine how activation within this regulation network is related to neurofeedback success.

Objective: To investigate the safety and efficacy of intermittent theta-burst stimulation (iTBS) in the treatment of motor symptoms in Parkinson disease (PD).Background: Progression of PD is characterized by the emergence of motor deficits, which even-

Animal studies suggest an involvement of CA3 and dentate gyrus (CA3&DG) in memory encoding and early retrieval and an involvement of CA1 in late retrieval, consolidation and recognition. The aim of this study was to test if similar associations could be found between hippocampal subfield volumes measured in vivo using a manual parcellation scheme and selected scores of the California Verbal Learning Test II (CVLTII): Total Immediate Free Recall Discriminability (IFRD), Short Free Recall Discriminability (SFRD), and Delayed Recall Discriminability (DRD). 50 elderly subjects (25 controls, 25 cognitively impaired subjects) had CVLTII and high resolution hippocampal MRI at 4T. Entorhinal cortex, subiculum, CA1, CA1-CA2 transition zone, and CA3&DG were manually marked on five slices in the anterior hippocampal body on the MRI. Pearson correlations followed by stepwise regression analysis were used to test for associations between subfield volumes and CVLTII. IFRD, SFRD, which are measures of encoding/early retrieval, were associated with CA3&DG, and DRD, which measures consolidation/late retrieval, with CA1. These preliminary findings demonstrate that subfield volumetry has the potential to study non invasively subfield specific memory functions.

Background The Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UDPRS) is a commonly used tool to measure Parkinson disease (PD) progression. Longitudinal changes in MDS-UPDRS scores in de novo PD have not been established. Objective Determine progression rates of MDS-UPDRS scores in de novo PD. Methods 362 participants from the Parkinson’s Progression Markers Initiative, a multicenter longitudinal cohort study of de novo PD, were included. Longitudinal progression of MDS-UPDRS total and subscale scores were modeled using mixed model regression. Results MDS-UPDRS scores increased in a linear fashion over five years in de novo PD. MDS-UPDRS total score increased an estimated 4.0 points/year, Part I 0.25 points/year, Part II 1.0 points/year, and Part III 2.4 points/year. Conclusions The expected average progression of MDS-UPDRS scores in de novo PD from this study can assist in clinical monitoring and provide comparative data for detection of disease modification in treatment trials.

Neuroleptic malignant syndrome (NMS) is a life-threatening idiosyncratic reaction to antipsychotic drugs characterized by fever, altered mental status, muscle rigidity, and autonomic dysfunction. It has been associated with virtually all neuroleptics, including newer atypical antipsychotics, as well as a variety of other medications that affect central dopaminergic neurotransmission. Although uncommon, NMS remains a critical consideration in the differential diagnosis of patients presenting with fever and mental status changes because it requires prompt recognition to prevent significant morbidity and death. Treatment includes immediately stopping the offending agent and implementing supportive measures, as well as pharmacological interventions in more severe cases. Maintaining vigilant awareness of the clinical features of NMS to diagnose and treat the disorder early, however, remains the most important strategy by which physicians can keep mortality rates low and improve patient outcomes.

Neuroimaging studies have elucidated some of the underlying physiology of spontaneous and voluntary eye blinking; however, the neural networks involved in eye blink suppression remain poorly understood. Here we investigated blink suppression by analyzing fMRI data in a block design and event-related manner, and employed a novel hypothetical time-varying neural response model to detect brain activations associated with the buildup of urge. Blinks were found to activate visual cortices while our block design analysis revealed activations limited to the middle occipital gyri and deactivations in medial occipital, posterior cingulate and precuneus areas. Our model for urge, however, revealed a widespread network of activations including right greater than left insular cortex, right ventrolateral prefrontal cortex, middle cingulate cortex, and bilateral temporo-parietal cortices, primary and secondary face motor regions, and visual cortices. Subsequent inspection of BOLD time-series in an extensive ROI analysis showed that activity in the bilateral insular cortex, right ventrolateral prefrontal cortex, and bilateral STG and MTG showed strong correlations with our hypothetical model for urge suggesting these areas play a prominent role in the buildup of urge. The involvement of the insular cortex in particular, along with its function in interoceptive processing, help support a key role for this structure in the buildup of urge during blink suppression. The right ventrolateral prefrontal cortex findings in conjunction with its known involvement in inhibitory control suggest a role for this structure in maintaining volitional suppression of an increasing sense of urge. The consistency of our urge model findings with prior studies investigating the suppression of blinking and other bodily urges, thoughts, and behaviors suggests that a similar investigative approach may have utility in fMRI studies of disorders associated with abnormal urge suppression such as Tourette syndrome and obsessive-compulsive disorder.

ObjectiveIsolated focal dystonia can spread to muscles beyond the initially affected body region, but risk of spread has not been evaluated in a prospective manner. Furthermore, body regions at risk for spread and the clinical factors associated with spread risk are not well characterised. We sought here to prospectively characterise risk of spread in recently diagnosed adult-onset isolated focal dystonia patients.MethodsPatients enrolled in the Dystonia Coalition with isolated dystonia affecting only the neck, upper face, hand or larynx at onset of symptoms were included. Timing of follow-up visits was based on a sliding scale depending on symptom onset and ranged from 1 to 4 years. Descriptive statistics, Kaplan-Meier survival curves and Cox proportional hazard regression models were used to assess clinical characteristics associated with dystonia spread.Results487 enrolled participants (68.3% women; mean age: 55.6±12.2 years) met our inclusion/exclusion criteria. Spread was observed in 50% of blepharospasm, 8% of cervical dystonia, 17% of hand dystonia and 16% of laryngeal dystonia cases. Most common regions for first spread were the oromandibular region (42.2%) and neck (22.4%) for blepharospasm, hand (3.5%) for cervical dystonia and neck for hand (12.8%) and laryngeal (15.8%) dystonia. Increased spread risk was associated with a positive family history (HR=2.18, p=0.012) and self-reported alcohol responsiveness (HR=2.59, p=0.009).ConclusionsInitial body region affected in isolated focal dystonia has differential risk and patterns of spread. Genetic factors likely influence the risk of spread. These findings can aid clinical prognostication and inform future investigations into potential disease-modifying treatments.