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Current rating scales for Tourette syndrome (TS) are limited by recollection bias or brief assessment periods. This proof-of-concept study aimed to develop a sensor-based paradigm to detect and classify tics.We recorded both electromyogram and acceleration data from seventeen TS patients, either when voluntarily moving or experiencing tics and during the modified Rush Video Tic Rating Scale (mRVTRS). Spectral properties of voluntary and tic movements from the sensor that captured the dominant tic were calculated and used as features in a support vector machine (SVM) to detect and classify movements retrospectively.Across patients, the SVM had an accuracy, sensitivity, and specificity of 96.69 ± 4.84%, 98.24 ± 4.79%, and 96.03 ± 6.04%, respectively, when classifying movements in the test dataset. Furthermore, each patient's SVM was validated using data collected during the mRVTRS. Compared to the expert consensus, the tic detection accuracy was 85.63 ± 15.28% during the mRVTRS, while overall movement classification accuracy was 94.23 ± 5.97%.These results demonstrate that wearable sensors can capture physiological differences between tic and voluntary movements and are comparable to expert consensus.Ultimately, wearables could individualize and improve care for people with TS, provide a robust and objective measure of tics, and allow data collection in real-world settings.

Background Impulsivity and impulse control disorders are common in Parkinson’s disease and lead to increased morbidity and reduced quality of life. Impulsivity is thought to arise from aberrant reward processing and inhibitory control, but it is unclear why deep brain stimulation of either the subthalamic nucleus (STN) or globus pallidus internus (GPi) affects levels of impulsivity. Our aim was to assess the role of the STN and GPi in impulsivity using invasive local field potential (LFP) recordings from deep brain stimulation electrodes. Methods We measured LFPs during a simple rewarding Go/NoGo paradigm in 39 female and male human patients with Parkinson’s disease manifesting variable amounts of impulsivity who were undergoing unilateral deep brain stimulation of either the STN (18 nuclei) or GPi (28 nuclei). We identified reward-specific LFP event-related potentials and correlated them to impulsivity severity. Results LFPs in both structures modulated during reward-specific Go and NoGo stimulus evaluation, reward feedback, and loss feedback. Motor and limbic functions were anatomically separable in the GPi but not in the STN. Across participants, LFP reward processing responses in the STN and GPi uniquely depended on the severity of impulsivity. Conclusions This study establishes LFP correlates of impulsivity within the STN and GPi regions. We propose a model for basal ganglia reward processing that includes the bottom-up role of the GPi in reward salience and the top-down role of the STN in cognitive control.

Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Background Deep brain stimulation (DBS) is an effective surgical therapy for individuals with essential tremor (ET). However, DBS operates continuously, resulting in adverse effects such as postural instability or dysarthria. Continuous DBS (cDBS) also presents important practical issues including limited battery life of the implantable neurostimulator (INS). Collectively, these shortcomings impact optimal therapeutic benefit in ET. Objective The goal of the study was to establish a physiology-driven responsive DBS (rDBS) system to provide targeted and personalized therapy based on electromyography (EMG) signals. Methods Ten participants with ET underwent rDBS using Nexus-D, a Medtronic telemetry wand that acts as a direct conduit to the INS by modulating stimulation voltage. Two different rDBS paradigms were tested: one driven by one EMG (single-sensor) and another driven by two or more EMGs (multi-sensor). The feature(s) used in the rDBS algorithms was the pow2er in the participant's tremor frequency band derived from the sensors controlling stimulation. Both algorithms were trained on kinetic and postural data collected during DBS off and cDBS states. Results Using established clinical scales and objective measurements of tremor severity, we confirm that both rDBS paradigms deliver equivalent clinical benefit as cDBS. Moreover, both EMG-driven rDBS paradigms delivered less total electrical energy translating to an increase in the battery life of the INS. Conclusions The results of this study verify that EMG-driven rDBS provides clinically equivalent tremor suppression compared to cDBS, while delivering less total electrical energy. Controlling stimulation using a dynamic rDBS paradigm can mitigate limitations of traditional cDBS systems.

Introduction Patients with Parkinson's disease (PD) are at increased risk for hospitalization and often experience worsening of PD when hospitalized. It is therefore important to identify strategies to prevent hospitalization. Methods Hospital encounter rates in different Parkinson's Foundation Centers of Excellence in United States, Canada, Israel and the Netherlands were analyzed as part of the Parkinson Foundation Parkinson's Outcomes Project (PF-POP). Multivariate logistic regression was used to estimate the odds ratio for hospitalization, adjusted for risk factors. Results Baseline age, disease duration, other relative than spouse/partner as care giver, cancer, arthritis, other comorbidities, falls, use of levodopa, use of dopamine agonist, use of COMT inhibitor, occupational therapy before the baseline visit, PDQ-39, MSCI total score and time between visits were significantly associated with the risk of hospital encounters. After adjustment for these factors, two centers had significantly lower odds for hospitalization admission and ER visit (minimum OR 0.3) and four centers had significantly higher odds (maximum OR 1.5) than the average center. Four centers had significantly lower hazard ratios for time to re-hospitalization compared to the average center. Reducing hospital admission rates in those centers with higher than average rates would reduce overall hospitalizations by 11%. Applied to PD patients over 65 nationwide this represents a potential for cost savings of greater than $1 billion over 48 months. Conclusion Encounter rates vary even across expert centers and suggest that practices carried out in some centers may reduce the risk of hospitalization. Further research will be necessary to identify these practices and implement them more widely to improve care for people with PD.

Introduction Tourette syndrome (TS) is a complex neuropsychiatric disorder. A small percentage of individuals with TS will persist to experience severe, refractory, and impairing tics. Deep brain stimulation (DBS) has been increasingly used for symptom management especially in these settings. In this article, we aim to evaluate the rate and reasons for removal or explantation of DBS hardware in TS patients. Methods Data was analyzed from patients enrolled in the Tourette Association of America's International Tourette Syndrome Registry and Database. Results Fifteen of 269 (5.6%) patients required removal of their DBS systems. The mean age at explantation was 33.8 years. In these cases we observed a rate of 1.9 explantations per year of follow up from implantation. None of the removals took place in the immediate post-operative period. Infection was the most common cause (46.7%). Only one patient received explantation for tic resolution. There were no significant associations between explantation and the presence of specific psychiatric comorbidities, including OCD, depression, anxiety, or ADHD. Discussion The rate of removal of 5.6% was lower than the previously reported rate in the TS DBS literature. Infections account for nearly half of the TS DBS explantations. No relationship to psychiatric comorbidities has been established.

Dystonic tremor (DT) is defined as the tremor in body parts affected by dystonia. Although deep brain stimulation (DBS) has been used to manage medically-refractory DT patients, its efficacy has not been well established. The objective of this study is to provide an up-to-date systematic review of DBS outcomes for DT patients. We conducted a literature search using Medline, Embase, and Cochrane Library databases in February 2020 according to the PRISMA guidelines. From 858 publications, we identified 30 articles involving 89 DT patients who received DBS of different targets. Thalamic DBS was the most common (n = 39) and improved tremor by 40–50% potentially in the long-term over five years with variable effects on dystonic symptoms. Globus pallidus internus (GPi), subthalamic, and subthalamic nucleus (STN) DBS improved both tremor and dystonic symptoms; however, data were limited. A few studies have reported better tremor and dystonia outcomes with combinations of different targets. Concerning adverse effects, gait/balance disorders, and ataxia seemed to be more common among patients treated with thalamic or subthalamic DBS, whereas parkinsonian adverse effects were observed only in patients treated with subthalamic or GPi DBS. Comparative benefits and limitations of these targets remain unclear because of the lack of randomized controlled trials. In conclusion, DBS of these targets may improve tremor with a variable effect on dystonia with different adverse effect profiles. The shortcomings in the literature include long-term motor outcomes, quality of life outcomes, optimal DBS targeting, and DBS programming strategy.

Chronic neurological diseases are the leading source of disability globally. Yet, our healthcare systems are not designed optimally to meet the needs of the many chronic neurological patients. Care is fragmented, with poor interdisciplinary collaboration and lack of timely access to services and therapies. Furthermore, care is typically reactive, and complex problems are managed inadequately due to lack of disease-specific expertise and insufficient use of non-pharmacological interventions. Treatment plans tend to focus on the disease rather than the individual living with it, and patients are insufficiently involved in clinical decision making. Utilising Parkinson’s disease as a model condition, we illustrate an integrated care concept with a patient-centred perspective that includes evidence-based solutions to tackle the limitations of current healthcare delivery for people with chronic neurological conditions. We anticipate that this integrated care model will improve the quality of lives of patients and create an attractive working environment for professionals, whilst being affordable for future generations.

Dystonia is an incurable movement disorder which can cause not only physical but also mental problems, leading to impaired health-related quality of life (HRQoL). For patients with dystonia refractory to medical treatment, deep brain stimulation (DBS) is a well-established surgical treatment. The objective of this systematic review is to provide a better understanding of HRQoL outcomes after DBS for dystonia. A search of the literature was conducted using Medline (PubMed), Embase, and Cochrane Library databases in May 2019. HRQoL outcomes after DBS along with motor outcomes were reported in a total of 36 articles involving 610 patients: 21 articles on inherited or idiopathic isolated dystonia, 5 on tardive dystonia, 3 on cerebral palsy, 2 on myoclonus-dystonia, 1 on X-linked dystonia-parkinsonism, and 3 on mixed cohorts of different dystonia subtypes. DBS improved motor symptoms in various subtypes of dystonia. Most studies on patients with inherited or idiopathic isolated dystonia showed significant improvement in physical QoL, whereas gains in mental QoL were less robust and likely related to the complexity of associated neuropsychiatric problems. HRQoL outcomes beyond 5 years remain scarce. Although the studies on patients with other subtypes of dystonia also demonstrated improvement in HRQoL after DBS, the interpretation is difficult because of a limited number of articles with small cohorts. Most articles employed generic measures (e.g. Short Form Health Survey-36) and this highlights the critical need to develop and to utilize sensitive and disease-specific HRQoL measures. Finally, long-term HRQoL outcomes and predictors of HRQoL should also be clarified.

Objective Essential tremor (ET) prominently affects the upper-limbs during voluntary movements, but can also affect the lower-limbs, head, and chin. Although deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of thalamus improves both clinical ratings and quantitative measures of tremor, no study has quantified effects of DBS on tremor across multiple body parts. Our objective was to quantify therapeutic effects of DBS across multiple body parts in ET. Methods We performed quantitative assessment of tremor in ET patients who had DBS for at least one year. We assessed tremor on and off VIM-stimulation using triaxial accelerometers on the upper-limbs, lower-limbs, head and chin during seated and standing tasks. Results VIM-DBS significantly reduced tremor, but there was no statistical difference in degree of tremor reduction across the measured effectors. Compared to healthy controls, ET patients treated with DBS showed significantly greater tremor power (4–8 Hz) across all effectors during seated and standing tasks. Conclusions VIM-DBS reduced tremor in ET patients. There was no significant difference in the degree of tremor reduction across the measured effectors. Significance This study provides new quantitative evidence that VIM-DBS is effective at reducing tremor across multiple parts of the body.

Background Physical therapy (PT) for cervical dystonia is not well studied, and the underlying physiological effects are not known. Methods We enrolled 26 subjects comprising of 16 cervical dystonia and 10 healthy controls for normative physiological data. We randomized cervical dystonia patients who reported suboptimal benefits on botulinum toxin (BoNT) injections to BoNT alone (BoNT arm) or BoNT plus PT (PT-BoNT arm). PT-BoNT arm received manual PT on the injection day followed by six weeks of home-exercise program. Home-exercise program comprised of stretching, range-of-motion and isometric exercises. The primary outcome was change from baseline in Toronto Western spasmodic torticollis rating scale (TWSTRS) that was recorded six weeks after exercise program. TWSTRS was video evaluated by blinded raters. We probed sensorimotor plasticity with transcranial magnetic stimulation (TMS) using a paired associative stimulation (PAS) paradigm. Results TWSTRS score improved (severity 31%, p = 0.002; pain 28%, p = 0.01) and PAS plasticity decreased (p = 0.01) in PT-BoNT arm compared to BoNT arm. PAS values for PT-BoNT arm were found to approach values of healthy control values. Change in PAS measure correlated significantly with TWSTRS change (severity, r = 0.56, p = 0.04; pain, r = 0.61, p = 0.03. TWSTRS disability score only approached significance (p = 0.14) when comparing the two treatment arms. Conclusion PT is a potential adjunct in patients with cervical dystonia who report suboptimal benefits with BoNT therapy. PT related benefits in cervical dystonia are likely mediated through modulation of sensorimotor plasticity.

INTRODUCTION: Performance tasks are presumed to have greater validity than rating scales in assessing day-to-day behaviors in Parkinson’s disease (PD). One such task is the revised Observed Tasks of Daily Living (OTDL-R), which has been used extensively in healthy older adults, and but not yet empirically examined in PD. Thus, the aims of the current study were to examine and determine the impact of cognitive, motor, and mood symptoms on OTDL-R performance in PD. METHOD: Nineteen non-demented PD patients and 18 healthy older adults (HC) were administered measures of mood and cognitive functioning, and the OTDL-R (subtests include medication and telephone use, and medication management). Clinical severity of PD was assessed using the H&Y stage, UPDRS, and Schwab and England functional disability scores. RESULTS: Mann Whitney U tests indicated the PD patients were significantly slower to complete the OTDL-R and performed worse on only the telephone use subtest, relative to the HC group. In the PD group, hierarchical regression analyses revealed memory, attention, and initiative/perseveration were uniquely associated with the financial management subtest, after controlling for motor severity (ps

Introduction Drawing on the seminal work of DeLong, Albin, and Young, we have now entered an era of basal ganglia neuromodulation. Understanding, re-evaluating, and leveraging the lessons learned from neuromodulation will be crucial to facilitate an increased and improved application of neuromodulation in human disease. Methods We will focus on deep brain stimulation (DBS) – the most common form of basal ganglia neuromodulation – however, similar principles can apply to other neuromodulation modalities. We start with a brief review of DBS for Parkinson's disease, essential tremor, dystonia, and Tourette syndrome. We then review hallmark studies on basal ganglia circuits and electrophysiology resulting from decades of experience in neuromodulation. The organization and content of this paper follow Dr. Okun's Lecture from the 2018 Parkinsonism and Related Disorders World Congress. Results Information gained from neuromodulation has led to an expansion of the basal ganglia rate model, an enhanced understanding of nuclei dynamics, an emerging focus on pathological oscillations, a revision of the tripartite division of the basal ganglia, and a redirected focus toward individualized symptom-specific stimulation. Though there have been many limitations of the basal ganglia “box model,” the construct provided the necessary foundation to advance the field. We now understand that information in the basal ganglia is encoded through complex neural responses that can be reliably measured and used to infer disease states for clinical translation. Conclusions Our deepened understanding of basal ganglia physiology will drive new neuromodulation strategies such as adaptive DBS or cell-specific neuromodulation through the use of optogenetics.

As the second most common progressive neurodegenerative disorder with increased prevalence in the aging population, Parkinson's disease (PD) affects more than 10 million individuals worldwide with approximately 60,000 new cases occurring each year only in the US. While daily living abilities deteriorate in people with PD, they spend a significant amount of time in their homes. Unfortunately, most existing guidelines for home modification design reflect a standardized, singular plan. This study aimed to demonstrate the feasibility of using a virtual reality (VR) system for persons with PD to virtually walk through different home modifications and to adapt and personalize interior features. A sample of 15 participants with idiopathic PD and 24 healthy adults ambulated on a pressure mat, while using a VR headset and hand controller. Both groups envisioned walking through a virtual doorway from a simulated bedroom into its attached bathroom. Design features for the intervention included doorway width and door-frame color. Each participant was randomly assigned to one of three intervention conditions: (1) standard design, (2) enhanced design, and (3) co-design. The codesign module allowed participants to manipulate design features using a hand controller. We recorded 4 movement variables. Participants completed three questionnaires assessing anxiety, system usability, and satisfaction. Healthy control adults revealed no differences in movement or subjective assessment between the three intervention conditions. However, there were significant differences in the PD group between co-design and the other conditions. The changes were appreciated in the baseline measures of gait distance and strikes as well as in the composite gait component score. This study showed that using VR as a participatory design tool for persons with PD is safe and feasible. Additionally, the self-determination of interior design conditions may possibly affect movement performance measures and merits additional controlled trials.

Advanced diffusion imaging which accounts for complex tissue properties, such as crossing fibers and extracellular fluid, may detect longitudinal changes in widespread pathology in atypical Parkinsonian syndromes. We implemented fixel-based analysis, Neurite Orientation and Density Imaging (NODDI), and free-water imaging in Parkinson's disease (PD), multiple system atrophy (MSAp), progressive supranuclear palsy (PSP), and controls longitudinally over one year. Further, we used these three advanced diffusion imaging techniques to investigate longitudinal progression-related effects in key white matter tracts and gray matter regions in PD and two common atypical Parkinsonian disorders. Fixel-based analysis and free-water imaging revealed longitudinal declines in a greater number of descending sensorimotor tracts in MSAp and PSP compared to PD. In contrast, only the primary motor descending sensorimotor tract had progressive decline over one year, measured by fiber density (FD), in PD compared to that in controls. PSP was characterized by longitudinal impairment in multiple transcallosal tracts (primary motor, dorsal and ventral premotor, pre-supplementary motor, and supplementary motor area) as measured by FD, whereas there were no transcallosal tracts with longitudinal FD impairment in MSAp and PD. In addition, free-water (FW) and FW-corrected fractional anisotropy (FAt) in gray matter regions showed longitudinal changes over one year in regions that have previously shown cross-sectional impairment in MSAp (putamen) and PSP (substantia nigra, putamen, subthalamic nucleus, red nucleus, and pedunculopontine nucleus). NODDI did not detect any longitudinal white matter tract progression effects and there were few effects in gray matter regions across Parkinsonian disorders. All three imaging methods were associated with change in clinical disease severity across all three Parkinsonian syndromes. These results identify novel extra-nigral and extra-striatal longitudinal progression effects in atypical Parkinsonian disorders through the application of multiple diffusion methods that are related to clinical disease progression. Moreover, the findings suggest that fixel-based analysis and free-water imaging are both particularly sensitive to these longitudinal changes in atypical Parkinsonian disorders.

Background Conventional deep brain stimulation (DBS) utilizes regular, high frequency pulses to treat medication-refractory symptoms in essential tremor (ET). Modifications of DBS pulse shape to achieve improved effectiveness is a promising approach. Objectives The current study assessed the safety, tolerability and effectiveness of square biphasic pulse shaping as an alternative to conventional ET DBS. Methods This pilot study compared biphasic pulses (BiP) versus conventional DBS pulses (ClinDBS). Eleven ET subjects with clinically optimized ventralis intermedius nucleus DBS were enrolled. Objective measures were obtained over 3 h while ON BiP stimulation. Results There was observed benefit in the Fahn-Tolosa Tremor Rating Scale (TRS) for BiP conditions when compared to the DBS off condition and to ClinDBS setting. Total TRS scores during the DBS OFF condition (28.5 IQR = 24.5–35.25) were significantly higher than the other time points. Following active DBS, TRS improved to (20 IQR = 13.8–24.3) at ClinDBS setting and to (16.5 IQR = 12–20.75) at the 3 h period ON BiP stimulation (p = 0.001). Accelerometer recordings revealed improvement in tremor at rest (χ2 = 16.1, p = 0.006), posture (χ2 = 15.9, p = 0.007) and with action (χ2 = 32.1, p= Conclusion BiP was safe, tolerable and effective on the tremor symptoms when tested up to 3 h. This study demonstrated the feasibility of applying a novel DBS waveform in the clinic setting. Larger prospective studies with longer clinical follow-up will be required.

Background Persons with Parkinson’s disease exhibit gait deficits during comfortable-pace overground walking and data from pressure sensitive mats have been used to quantify gait performance. The Primary Gait Screen is a new assessment which includes gait initiation, overground walking, turning, and gait termination. Although overground assessments are useful, the Primary Gait Screen offers a more complex evaluation than traditional gait assessments. Research question Is the overground walking portion of the Primary Gait Screen comparable to traditional gait assessments? Methods Persons with Parkinson’s disease (N = 175; 47 F, 128 M; 67 ± 9 yrs) prospectively completed 4 passes at a self-selected speed and two trials of the Primary Gait Screen on an 8 m long pressure-sensing mat. Spatiotemporal gait variables were computed and a repeated-measures MANOVA with a Bonferroni correction compared the spatiotemporal variables from the Primary Gait Screen to the self-selected trials: gait velocity, cadence, step length, step time, and stride length. Results The analyses failed to detect differences between the Primary Gait Screen and self-selected trials for gait velocity, step length, or stride length (p > .01). Post-hoc tests revealed decreased cadence and increased step time were the only differences between the Primary Gait Screen trials and the self-selected trial (p Significance Differences seen in cadence and step time during the Primary Gait Screen may be attributed to patients’ strategy, but are likely not clinically meaningful. The Primary Gait Screen appears to be a comparable assessment of overground walking in persons with Parkinson’s disease, and may be a useful and accurate clinical assessment of walking.

Introduction Recent evidence suggests deep brain stimulation can alter impulse control. Our objective was to prospectively evaluate the effects of subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation on impulse control disorders (ICDs) in the setting of a conservative dopamine reduction strategy. Methods Patients (n = 37) undergoing de novo, unilateral STN or GPi DBS lead implantation were evaluated pre-operatively and 6–12 months post-operatively for the presence of ICDs using the Questionnaire for Impulsivity in Parkinson's disease (QUIP) and by clinical interview. Results Of the patients enrolled, 23 underwent electrode implantation in the globus pallidus internus and 14 were implanted in the subthalamic nucleus. Mean time to long term follow-up was 9.7 ± 2.4 months. Post-operative LEDD was not significantly lower than pre-operative LEDD (pre-op: 1238.53 ± 128.47 vs. post-op: 1178.18 ± 126.43, p = 0.2972, paired t-test). Mean QUIP scores were significantly lower at follow up compared to pre-operative baseline (1.51 ± 0.45 vs. 2.51 ± 0.58, p = 0.0447, paired t-test). Patients with ICDs pre-operatively (n = 14, 37.8%) had significant improvement in QUIP scores at follow-up (6.00 ± 0.94 vs. 2.64 ± 0.98, p = 0.0014, paired t-test). Improvement was not uniform across the cohort: 1 patient with ICD at baseline developed worsening symptoms, and 4 patients with no ICD pre-operatively developed clinically significant ICDs post-operatively. Conclusion When LEDD is relatively unchanged following STN or GPi DBS for PD, ICD symptoms tend toward improvement, although worsening and emergence of new ICDs can occur. In the setting of stable LEDD, these findings suggest that the intrinsic effects of DBS may play a significant role in altering impulsive behavior.

Persons with Parkinson’s disease (PD) are typically more susceptible than healthy adults to impaired performance when two tasks (dual task interference) are performed simultaneously. This limitation has by many experts been attributed to limitations in cognitive resources. Nearly all studies of dual task performance in PD employ walking or balance-based motor tasks, which are commonly impaired in PD. These tasks can be performed using a combination of one or two executive function tasks. The current study examined whether persons with PD would demonstrate greater dual task effects on cognition compared to healthy older adults (HOAs) during a concurrent cycling task. Participants with and without PD completed a battery of 12 cognitive tasks assessing visual and verbal processing in the following cognitive domains: speed of processing, controlled processing, working memory and executive function. Persons with PD exhibited impairments compared to healthy participants in select tasks (i.e., 0-Back, 2-Back and operation span). Further, both groups unexpectedly exhibited dual task facilitation of response times in visual tasks across cognitive domains, and improved verbal recall during an executive function task. Only one measure, 2-back, showed a speed-accuracy trade-off in the dual task. These results demonstrate that, when paired with a motor task in which they are not impaired, people with PD exhibit similar dual task effects on cognitive tasks as HOAs, even when these dual task effects are facilitative. More generally, these findings demonstrate that pairing cognitive tasks with cycling may actually improve cognitive performance which may have therapeutic relevance to cognitive decline associated with aging and PD pathology.

Neuronal population responses can vary across trials as a result of differences in the relative timing of internal brain processes. In this issue of Neuron, Williams et al. (2020) present an algorithm for inferring and inverting such trial-to-trial differences, thereby revealing an a priori hidden, precise temporal structure of population responses.

Highlights • A functional targeting method for centromedian-parafascicular nucleus of thalamus. • Strong local field potentials that correlate with position during stimuli onset. • Differentiable signal along the trajectory of the electrode in thalamus., Background The centromedian-parafascicular (Cm-Pf) complex of the thalamus is a common deep brain stimulation (DBS) target for treatment of Tourette syndrome (TS). Currently, there are no standardized functional intraoperative neurosurgical targeting approaches. Collectively, these issues have led to variability in DBS lead placement. Therefore, more defined methods are needed to improve targeting accuracy. Objective The objective of this observational study was to develop and to verify a functional mapping task capable of differentiating the Cm-Pf region from the nearby ventral intermediate (Vim) nucleus region of the thalamus. The overarching goal was to improve the reproducibility of DBS targeting in the Cm-Pf region. Methods Seven TS patients completed a modified Go/NoGo task (five in the post-operative setting and two in the intra-operative setting). Post-operative neural signals from Cm-Pf region were collected using sensing-enabled implanted neural stimulators, and intraoperative neural signals from the Cm-Pf region were collected using an external amplifier. Event-related potential (ERP) features were identified by using the grand-average of stimulus onset signals derived from the postoperative participants. These features were correlated with anatomical locations for the specific electrode recordings. The same features were extracted from the intraoperative patients in order to verify electrode positions in the operating room environment. Results Two features – a positive and a negative deflection – were identified in the average ERP from the post-operative participants. The peak amplitudes of both features were significantly correlated with the electrode depth position (p = 0.025 for positive deflection and p = 0.039 for negative deflection). The same result was reproduced intra-operatively in the two most recent patients, where more ventral electrode contacts revealed stronger peak amplitudes in comparison to the dorsal electrode contacts. Conclusion This process was used to physiologically confirm accurate lead placement in the operating room setting. The modified Go/NoGo task elicited robust neural responses in the Cm-Pf region however the signal was not present in the Vim nucleus region of thalamus along the DBS electrode trajectory. We conclude that the differences in ERP responses may be a potentially novel LFP based functional approach for future targeting of the Cm-Pf complex for TS DBS.

Impairments in acoustically cued repetitive finger movement often emerge at rates near to and above 2Hz in persons with Parkinson's Disease (PD) in which some patients move faster (hastening) and others move slower (bradykinetic). The clinical features impacting this differential performance of repetitive finger movement remain unknown. The purpose of this study was to compare repetitive finger movement performance between the more and less affected side, and the difference in clinical ratings among performance groups. Forty-one participants diagnosed with idiopathic PD completed an acoustically cued repetitive finger movement task while "on" medication. Eighteen participants moved faster, 10 moved slower, and 13 were able to maintain the appropriate rate at rates above 2Hz. Clinical measures of laterality, disease severity, and the UPDRS were obtained. There were no significant differences between the more and less affected sides regardless of performance group. Comparison of disease severity, tremor, and rigidity among performance groups revealed no significant differences. Comparison of posture and postural instability scores revealed that the participants that demonstrated hastening had worse posture and postural instability scores. Consideration of movement rate during the clinical evaluation of repetitive finger movement may provide additional insight into varying disease features in persons with PD.

Introduction Dopamine and glutamate are crucial neurotransmitters in Parkinson disease (PD). While recent large meta-analyses reported that genetic variation of dopamine (DRD2, DRD3) and glutamine (NMDA, GRIN2B) neurotransmitter receptors was not associated with PD risk, they could conceivably influence PD phenotype. We studied the association of these receptor polymorphisms relating to PD age of onset. Methods There were 664 PD patients and 718 controls, all Caucasian, with stored DNA at Mayo Clinic, Jacksonville, Florida. Genotyping was performed for DRD2 (Taq 1A, rs1800497), DRD3 (rs6280), and NMDA (GRIN2B, rs7301328) polymorphisms with ABI Taqman assays. Single nucleotide polymorphism associations with age of onset were evaluated using dominant, recessive, and additive genotypic models. Results DRD3 variant carriers had an approximate 4.4-year decrease in mean age of onset when both copies of the minor allele were present (P = 0.0034) and an approximate 1.5-year decrease in mean age at onset for every additional minor allele (P = 0.023) (recessive and additive models, respectively). There was no association with age of onset for DRD2 or GRIN2B under any statistical model (all P ≥ 0.22). Conclusions The DRD3 (rs6280) polymorphism, but not DRD2 (Taq1A) or GRIN2B, influences younger PD age of onset in the US Caucasian population. Validation of these findings in larger studies with other ethnic groups is indicated.

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. Deep brain stimulation (DBS) is an emerging therapy for severe cases of TS. We studied two patients with TS implanted with bilateral Medtronic Activa PC + S DBS devices, capable of chronic recordings, with depth leads in the thalamic centromedian–parafascicular complex (CM-PF) and subdural strips over the precentral gyrus. Low-frequency (1–10 Hz) CM-PF activity was observed during tics, as well as modulations in beta rhythms over the motor cortex. Tics were divided into three categories: long complex, complex, and simple. Long complex tics, tics involving multiple body regions and lasting longer than 5 s, were concurrent with a highly detectable thalamocortical signature (average recall [sensitivity] 88.6%, average precision 96.3%). Complex tics were detected with an average recall of 63.9% and precision of 36.6% and simple tics an average recall of 39.3% and precision of 37.9%. The detections were determined using data from both patients., Highlights • Low-frequency (

Objective Deep brain stimulation (DBS) is an effective therapy for the treatment of a number of movement and neuropsychiatric disorders. The effectiveness of DBS is dependent on the density and location of stimulation in a given brain area. Adjustments are made to optimize clinical benefits and minimize side effects. Until recently, clinicians would adjust DBS settings using a voltage mode, where the delivered voltage remained constant. More recently, a constant-current mode has become available where the programmer sets the current and the stimulator automatically adjusts the voltage as impedance changes. Methods We held an expert consensus meeting to evaluate the current state of the literature and field on constant-current mode versus voltage mode in clinical brain-related applications. Results/Conclusions There has been little reporting of the use of constant-current DBS devices in movement and neuropsychiatric disorders. However, as impedance varies considerably between patients and over time, it makes sense that all new devices will likely use constant current.

Previous research has indicated increased functional connectivity between subthalamic nucleus (STN) and sensorimotor cortex in off-medication Parkinson's disease (PD) compared with control subjects. It is not clear if the increase in functional connectivity between STN and sensorimotor cortex occurs in de novo PD, which is before patients begin dopamine therapy. Resting-state functional magnetic resonance imaging was carried out in 20 de novo (drug naïve) patients with PD (Hoehn and Yahr stage: I-II), 19 patients with moderate PD (Hoehn and Yahr stage: II-III), and 19 healthy controls. The functional connectivity analysis in de novo and moderate PD patients focused on the connectivity of the more affected STN and the sensorimotor cortex. Using resting-state functional connectivity analysis, we provide new evidence that people with de novo PD and off-medicated moderate PD have increased functional connectivity between the more affected STN and different regions within the sensorimotor cortex. The overlapping sensorimotor cortex found in both de novo and moderate PD had functional connectivity values that correlated positively with the Unified Parkinson's Disease Rating Scale part III. This key finding suggests that changes in functional connectivity between STN and sensorimotor cortex occur early in the disease following diagnosis and before dopamine therapy.

Introduction DBS is a therapeutic option for patients with Parkinson disease (PD), tremor and dystonia. In patients who experience suboptimal clinical results with conventional programming (monopolar, double monopolar or bipolar settings), interleaved pulses can sometimes be used to provide differential therapeutic benefits with the possibility of fewer side effects. Interleaving allows a clinician to define two “programs” that automatically alternate. The goal of this paper is to 1) present clinical scenarios where DBS interleaving was used across two clinics to provide improved symptom control in three patients with suboptimal results from conventional programming; 2) address the potential mechanisms of interleaving; and 3) provide practical tips on the use of interleaving. Methods Three patients were formally compared for therapeutic benefit on interleaved and conventional parameter settings. Results Interleaving is most likely to be useful in two clinical scenarios: 1) different contacts are beneficial for specific symptoms, but each at a different stimulation amplitude; or 2) symptoms are resolved incompletely, and further voltage increase is limited by side effects. The factors underpinning the differences in outcomes with interleaving are unknown but may be highly dependent on specific symptoms and to electrode positioning. Interleaving is a relatively new programming platform and there is no data to demonstrate long-term benefits. Conclusions Interleaving is a tool that may augment outcomes, and possibly obviate the need for surgical revisions, although in our experience across two large centers it has been effective for only a small number of patients.

BACKGROUND Aspiration pneumonia is a leading cause of death in people with Parkinson disease (PD). The pathogenesis of these infections is largely attributed to the presence of dysphagia with silent aspiration or aspiration without an appropriate cough response. The goal of this study was to test reflex cough thresholds and associated urge-to-cough (UTC) ratings in participants with PD with and without dysphagia. METHODS Twenty participants with PD were recruited for this study. They completed a capsaicin challenge with three randomized blocks of 0, 50, 100, and 200 μM capsaicin and rated their UTC by modified Borg scale. The concentration of capsaicin that elicited a two-cough response, total number of coughs, and sensitivity of the participant to the cough stimulus (UTC) were measured. The dysphagia severity of participants with PD was identified with the penetration-aspiration scale. RESULTS Most participants with PD did not have a consistent two-cough response to 200 μM capsaicin. UTC ratings and total number of coughs produced at 200 μM capsaicin were significantly influenced by dysphagia severity but not by general PD severity, age, or disease duration. Increasing levels of dysphagia severity resulted in significantly blunted cough sensitivity (UTC). CONCLUSIONS UTC ratings may be important in understanding the mechanism underlying morbidity related to aspiration pneumonia in people with PD and dysphagia. Further understanding of decreased UTC in people with PD and dysphagia will be essential for the development of strategies and treatments to address airway protection deficits in this population.

Introduction The Parkinson's disease questionnaire-39 (PDQ-39) is a common measure of health related quality of life (HRQoL) that is widely used with Parkinson disease (PD) patients. Previous evidence suggests that the PDQ-39 reflects at least 8 dimensions (i.e., Emotion, Cognitions, Mobility, etc). To date, little research has examined the external/convergent validity of the Cognitions and Emotional Well-being domains of the PDQ-39.

In 1999, Deep Brain Stimulation (DBS) was introduced as a new therapeutic approach for patients suffering from refractory Tourette syndrome (TS). This initial target was located in the medial part of the thalamus, based on the good results of thalamotomies described by Hassler and Dieckmann (1970) . Up until now, more than 100 cases have been published worldwide of Tourette patients receiving DBS. The targets have been diverse and can be divided into four brain areas: the thalamus (medial parts, and ventral parts), the globus pallidus internus (posteroventrolateral part, and anteromedial part), the globus pallidus externus, and the internal capsule/nucleus accumbens. The subthalamic nucleus has also been suggested as a potential target for DBS in TS, based on the good effect of DBS on tics in a patient suffering from Parkinson׳s disease and TS. In the majority of cases, there was a clear effect on tics. The effect on associated behavioural disorders varies. Although stimulation-induced unwanted effects have been described, severe complications are rare and include two small haematomas at the tip of one electrode. Serious and lasting side effects or complications are rare. Although stimulation-induced and mainly transient unwanted effects have been described, the positive effect seems clearly to predominate. The majority of published studies include only a small number of patients. This underlines the importance of all cases being published, and that ideally the same protocol be followed so that results can be compared. A strict selection of patients and a standardized evaluation of the effects on tics, associated behavioural disorders, complications and exact position of the electrodes are therefore of great importance. The actual published reports suggest that the best effects can be obtained with DBS of the thalamus, and the anteromedial part of the globus pallidus internus.

Objectives Deep brain stimulation (DBS) has been established as a safe, effective therapy for movement disorders (Parkinson's disease, essential tremor, etc.), and its application is expanding to the treatment of other intractable neuropsychiatric disorders including depression and obsessive-compulsive disorder (OCD). Several published studies have supported the efficacy of DBS for severely debilitating OCD. However, questions remain regarding the optimal anatomic target and the lack of a bedside programming paradigm for OCD DBS. Management of OCD DBS can be highly variable and is typically guided by each center's individual expertise. In this paper, we review the various approaches to targeting and programming for OCD DBS. We also review the clinical experience for each proposed target and discuss the relevant neuroanatomy. Materials and Methods A PubMed review was performed searching for literature on OCD DBS and included all articles published before March 2012. We included all available studies with a clear description of the anatomic targets, programming details, and the outcomes. Results Six different DBS approaches were identified. High-frequency stimulation with high voltage was applied in most cases, and predictive factors for favorable outcomes were discussed in the literature. Conclusion DBS remains an experimental treatment for medication refractory OCD. Target selection and programming paradigms are not yet standardized, though an improved understanding of the relationship between the DBS lead and the surrounding neuroanatomic structures will aid in the selection of targets and the approach to programming. We propose to form a registry to track OCD DBS cases for future clinical study design.

Introduction: Deep Brain Stimulation (DBS) of thalamus in essential tremor (ET) is effective for the treatment of contralateral tremors. Bilateral DBS controls tremors on both sides but is associated with increased morbidity and risks. We evaluated if unilateral surgery had ipsilateral benefits on tremors and thus could be a potentially safer alternative to bilateral DBS. Methods: Medication refractory ET patients undergoing unilateral thalamic DBS were included and longitudinally followed. Tremor rating scale was used to record total motor, arm tremor and activities of daily living (ADL) scores at baseline, six months and at last visit (three or more years after surgery). Postoperative scores were recorded with DBS turned OFF and ON. Results: Twenty-two patients with a mean follow-up 3.4 � 0.14 years were enrolled. When baseline scores were compared to scores with the DBS turned ON, significant improvements were noted in total tremor (40%), ADL (67%) and arm tremor scores both on the ipsilateral and the contralateral side at six months and at the last visit of follow-up (all p < 0.05). Ipsilateral arm tremor (w56%) improvements were milder compared to the contralateral side (w73%) tremors. Conclusion: Unilateral thalamic DBS in ET demonstrates significant long-term benefits for ipsilateral arm tremors and can be offered to higher risk and to select patients.

Holmes' tremor (rubral or midbrain outflow tremor) refers to a hyperkinetic movement disorder characterized by mild resting and more severe postural and action tremor often with associated brainstem symptoms, dystonia and cerebellar deficits. This syndrome should prompt lesional evaluation with neuroimaging focused on the dorsal midbrain, cerebellar outflow tracts, and thalamus. Herein we report a 26-year-old previously healthy male who presented with 4 years of progressive horizontal diplopia, right Parinaud syndrome, and appendicular ataxia. Neuroimaging revealed a right dorsal midbrain enhancing lesion which completely resolved with intravenous methylprednisolone prompting a diagnosis of neuroinflammatory syndrome. Subsequent clinical and radiographic evaluations, however, revealed steadily progressive left dorsal midbrain syndrome with an expansile enhancing lesion which culminated 4 years from symptom onset with a right upper extremity low-frequency rest, postural and action tremor, ataxic dysarthria, and mild right dystonia with dysdiadochokinesia. Uncomplicated brainstem biopsy confirmed intracranial germinoma and the patient underwent definitive radiation therapy with dramatic radiographic response and partial clinical improvement. This case, which to our knowledge is only the second report of intracranial germinoma presenting as Holmes' tremor, highlights the critical importance of definitive tissue diagnosis in the evaluation of lesional brainstem pathology presenting as Holmes' tremor. Steroid responsiveness can be seen in non-inflammatory pathology including intracranial germinoma. Prompt evaluation and appropriate treatment are important as Holmes' tremor responds poorly to symptomatic therapies and response to radiation therapy is favorable for germinomas.

Essential tremor (ET) is a common tremor disorder affecting postural/action tremor of the upper extremities and midline. Recent research revealed a cerebellar-like deficit during tandem gait in persons with ET, though spatiotemporal variability during normal gait in ET has been relatively ignored. The first purpose of this study was to investigate gait variability magnitude and structure in ET as compared to healthy older adults (HOA). To address this issue, 11 ET and 11 age-matched HOAs walked on a treadmill for five minutes at preferred walking speeds. HOAs walked for an additional minute while speed-matched to an ET participant. The second purpose was to describe the clinical correlates of gait variability in this population. To address this aim, 31 persons with ET walked on a treadmill for five minutes and completed the Fahn-Tolosa-Marin Tremor Rating Scale. Gait variability magnitude was derived by calculating coefficients of variation in stride length, stride time, step length, step time, and step width. Gait variability structure was derived using a detrended fluctuation analysis technique. At preferred walking speeds, ET participants walked significantly slower with significantly increased variability magnitude in all five spatiotemporal gait parameters. At speed-matched walking, ET participants exhibited significantly higher step width variability. Gait variability structure was not different between groups. We also observed that gait variability magnitude was predicted by severity of upper extremity and midline tremors. This study revealed that self-selected gait in ET is characterized by high variability that is associated with tremor severity in the upper extremity and midline.

Gait initiation is a transitional task involving a voluntary shift from a static, stable position to a relatively less-stable state of locomotion. During gait initiation, anticipatory postural adjustments precede stepping in order to generate forward momentum while balance is maintained. While deficits in gait initiation are frequently reported for persons with Parkinson’s disease, there is a paucity of information regarding gait initiation performance in persons with Essential Tremor. We investigated anticipatory postural adjustments and spatiotemporal characteristics of gait initiation in persons with Essential Tremor and compared them to persons with Parkinson’s disease as well as age-matched neurologically-healthy adults. Twenty-four persons with Essential Tremor, 31 persons with Parkinson’s disease, and 38 age-matched controls participated. We compared anterior-posterior and mediolateral center of pressure movements and spatiotemporal stepping characteristics during gait initiation among the three groups using Mann-Whitney U-tests with Bonferroni corrections for multiple comparisons and one-way ANOVAs. Persons with Parkinson’s disease demonstrated significantly reduced displacement and velocity of the center of pressure during early phases of anticipatory postural adjustments relative to controls. Displacement of the center of pressure was also reduced in persons with Essential Tremor, although at a later stage of the gait initiation process. Persons with Parkinson’s disease and Essential Tremor demonstrated similar reductions in step length during gait initiation when compared to controls. Persons with Parkinson’s disease and Essential Tremor exhibit different deficits in gait initiation when compared to healthy older adults. Therefore, this study provides further evidence differentiating motor control features in these movement disorders.

Essential tremor (ET) is one of the most common movement disorders. Normally ET affects the distal upper extremities, but it can also be accompanied by midline symptoms. Ventralis intermedius (VIM) thalamic deep brain stimulation (DBS) has been shown to be effective in reducing hand tremor, but its effects on head tremor have been inconsistent.Twenty-nine DBS patients with a diagnosis of ET met inclusion criteria. All implantations targeted VIM. The factors examined included age, gender, disease duration, presence or absence of head tremor, handedness, and the Fahn-Tolosa-Marin rating scale (TRS). This analysis specifically focused on TRS head tremor sub-scores at baseline, 6 months and 12 months post-DBS. Additionally, DBS lead entry angles were examined.Twenty-three ET patients underwent unilateral DBS and six underwent staged bilateral DBS. At both 6 and 12 months following DBS, stimulation resulted in diminished head tremor (ON vs OFF; p 0.0001). The most important predictor of head tremor suppression was the entry angle of the DBS lead in the sagittal projection relative to the AC-PC axial plane (AC-PC angle). Head tremor reduction was greater among more vertical AC-PC angles.A more vertical AC-PC angle of the DBS lead trajectory was associated with improved head tremor suppression. Further studies will be necessary to confirm this potentially important finding.

Deep brain stimulation (DBS) has emerged as an important and potentially powerful treatment option for the management of carefully selected patients with advanced Parkinson's disease (PD) who are not adequately controlled by standard medication therapy. Though considerable advances have been made, the mechanisms underlying the therapeutic effects of DBS remain unclear despite its clinical efficacy. It is now widely held that both excitation and inhibition can occur secondary to stimulation, and it is suspected that abnormal synchronized oscillations may also be important in the mechanism of DBS. Other potentially important processes, including blood flow changes, local and upstream neurogenesis, and the modulation of neurotransmitters through stimulation of bordering astrocytes are also being investigated. Recent research has suggested that the temporal pattern of DBS stimulation is also an important variable in DBS neuromodulation, yet the extent of its influence on DBS efficacy has yet to be determined. As high stimulation frequency alone does not appear to be sufficient for optimal symptom suppression, attention to stimulation pattern might lead to more effective symptom control and reduced side effects, possibly at a lower frequency. Stimulation pattern may be potentially amenable to therapeutic modulation and its role in the clinical efficacy of DBS should be addressed through further focus and research.

To investigate the ability of the Timed UpGo test to identify patients with Parkinson's disease at risk for a fall.Cross-sectional cohort study.Sixteen participating National Parkinson's Foundation Centers of Excellence.A query yielded a total of 2985 records (1828 men and 1157 women). From these, 884 were excluded because of a lack of crucial information (age, diagnosis, presence of deep brain stimulation, disease duration, inability of performing the Timed UpGo test without assistance) at the time of testing, leaving 2097 patients included in the analysis.Not applicable.The primary outcome measure for this study was falls. The chief independent variable was the Timed UpGo test.The initial model examined the prediction of falls from the Timed UpGo test, adjusting for all study covariates. The estimated models in the imputed data sets represented a significant improvement above chance (χ(2) range [df=17], 531.29-542.39, P.001), suggesting that 74% of participants were accurately classified as a faller or nonfaller. The secondary model in which the question of whether the effect of Timed UpGo test was invariant across disease severity demonstrated 75% of participants were accurately classified as a faller or nonfaller. Additional analysis revealed a proposed cut score of 11.5 seconds for discrimination of those who did or did not fall.The findings suggest that the Timed UpGo test may be an accurate assessment tool to identify those at risk for falls.

Background Subthalamic (STN) and globus pallidus (GP) deep brain stimulation (DBS) have been previously shown to be efficacious in the treatment of selected Parkinson patients with medication resistant motor fluctuations and/or tremor. Deep brain stimulation of the STN has been implicated with more cognitive and mood side effects as compared to GP DBS; however, more studies are needed to better understand possible target differences. Previously, Mikos et al. [1] reported worsening of verbal fluency depending on the stimulation location within the STN region. Objective/hypothesis The current study applied the methods used by Mikos et al. (2011) to a different sample of Parkinson patients who underwent GP DBS. Based on differences in the size and functional somatotopy between structures (GP 412 mm3 vs. STN 167 mm3), we hypothesized that there would be a less robust relationship between volume of tissue activated, fluency performance, and stimulation contact within the GP compared to what was reported in the STN. Methods Patient-specific DBS models were created and the volume of tissue activated within the GP was calculated. These data were correlated with patients' verbal fluency performance at dorsal, optimal, and ventral stimulation contacts. Results In contrast to STN findings, there was no significant relationship between stimulation location and fluency performance in patients who received GP DBS. Conclusion(s) These results suggest that fluency may be less sensitive to stimulation location in the globus pallidus and thus there may be more flexibility in terms of DBS programming with GP DBS patients.

Objectives: To screen for potentially underreported behavioral changes in patients with idiopathic Parkinson's disease (PD) pre- and post-deep brain stimulation (DBS), a retrospective data base review was performed. Methods: In total, 113 patients who underwent unilateral or bilateral DBS at the University of Florida in either subthalamic nucleus or globus pallidus internus for PD were screened for behavioral issues by asking about the presence or absence of seven neuropsychiatric symptoms (panic, fear, paranoia, anger, suicidal flashes, crying, and laughing). Results: There was a high prevalence of fear (16.3%), panic (14.0%), and anger (11.6%) at baseline in this cohort. In the first six months following DBS implantation, anger (32.6%), fear (26.7%), and uncontrollable crying (26.7%) were the most frequent symptoms reported. Those symptoms also were present following six months of DBS surgery (30.2%, 29.1%, and 19.8%, respectively). New uncontrollable crying occurred more in the acute postoperative stage (less than or equal to six months) (p= 0.033), while new anger occurred more in the chronic postoperative stage (greater than six months) (p= 0.017). The frequency of uncontrollable laughing significantly increased with bilateral DBS (p= 0.033). Conclusions: Many of the neuropsychiatric issues were identified at preoperative baseline and their overall occurrence was more than expected. There was a potential for worsening of these issues post-DBS. There were subtle differences in time course, and in unilateral vs. bilateral implantations. Clinicians should be aware of these potential behavioral issues that may emerge following DBS therapy, and should consider including screening questions in preoperative and postoperative interviews. Standardized scales may miss the presence or absence of these clinically relevant issues.

Background Coordination between the upper and lower extremities is important to providing dynamic stability during human gait. Though limited, previous research has suggested that interlimb coordination may be impaired in persons with Parkinson's disease. We extend this previous work using continuous analytical techniques to enhance our understanding of interlimb coordination during gait in persons with Parkinson's disease. Methods Eighteen adults with Parkinson's disease and fifteen healthy older adults walked overground while undergoing three-dimensional motion capture. Ipsilateral and contralateral interlimb coordination between the sagittal shoulder and hip angles was assessed using cross-covariance techniques. Independent samples and paired samples t-tests compared measures of interlimb coordination between groups and between sides within the participants with Parkinson's disease, respectively. Pearson's correlations were applied to investigate associations between interlimb coordination measures and subscores of gait, posture, and bradykinesia on the Unified Parkinson's Disease Rating Scale. Findings Ipsilateral and contralateral interlimb coordination was reduced in persons with Parkinson's disease compared to the healthy older adults. Ipsilateral coordination between the upper and lower extremities more affected by disease was found to be negatively associated with clinical scores of gait and posture. Interlimb coordination was not significantly associated with clinical measures of bradykinesia. Interpretation Persons with Parkinson's disease exhibit reduced interlimb coordination during gait when compared to healthy older adults. These reductions in coordination are related to clinically-meaningful worsening of gait and posture in persons with PD and coordination of arm and leg movements should be considered in future research on gait therapy in this population.