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The effect of a precue on improving movement initiation (i.e., reaction time; RT) is well understood, whereas its influence on movement execution (i.e., movement time; MT) has rarely been examined. The current study investigated the influence of a directional precue (i.e., left vs. right) on the RT and MT of simple and discrete bi-directional movements in a large sample of Parkinson's disease patients and healthy control participants. Both patients and controls were tested twice, with testing sessions separated by 2 hours. Patients were tested first following an overnight levodopa withdrawal and again after they had taken their medication. Both patients and controls demonstrated a significant RT improvement when information was provided in advance. MT in both healthy participants and medicated patients was, however, slower with the provision of advance information, while unmedicated patients showed no significant MT effects. These results suggest that while the basal ganglia may not be involved in motor program selection, they may dynamically modulate movement execution. [ABSTRACT FROM AUTHOR]

Objective: Compared with motor deficits, sensory information processing in Parkinson's disease (PD) is relatively unexplored. While there is increasing interest in understanding the sensory manifestations of PD, the extent of sensory abnormality in PD has remained relatively unexplored. Furthermore, most investigations on the sensory aspects of PD involve motor aspects, causing confounding results. As sensory deficits often arise in early PD development stages, they present a potential technological target for diagnosis and disease monitoring that is affordable and accessible. Considering this, the current study's aim is to assess visual spatiotemporal perception independent of goal directed movements in PD by designing and using a scalable computational tool., Methods: A flexible 2-D virtual reality environment was created to evaluate various cases of visual perception. Using the tool, an experimental task quantifying the visual perception of velocity was tested on 37 individuals with PD and 17 age-matched control participants., Results: PD patients, both ON and OFF PD therapy, displayed perceptual impairments (p = 0.001 and p = 0.008, respectively) at slower tested velocity magnitudes. These impairments were even observed in early stages of PD (p = 0.015)., Conclusion: Visual velocity perception is impaired in PD patients, which suggests impairments in visual spatiotemporal processing occur in PD and provides a promising modality to be used with disease monitoring software., Significance: Visual velocity perception shows high sensitivity to PD at all stages of the disease. Dysfunction in visual velocity perception may contribute to observed motor dysfunction in PD., Competing Interests: Competing Interests The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Integration of multi-modal sensory inputs and modulation of motor outputs based on perceptual estimates is called Sensorimotor Integration (SMI). Optimal functioning of SMI is essential for perceiving the environment, modulating the motor outputs, and learning or modifying motor skills to suit the demands of the environment. Growing evidence suggests that patients diagnosed with Parkinson's Disease (PD) may suffer from an impairment in SMI that contributes to perceptual deficits, leading to motor abnormalities. However, the exact nature of the SMI impairment is still unclear. This study uses a robot-assisted assessment tool to quantitatively characterize SMI impairments in PD patients and how they affect voluntary movements. A set of assessment tasks was developed using a robotic manipulandum equipped with a virtual-reality system. The sensory conditions of the virtual environment were varied to facilitate the assessment of SMI. A hundred PD patients (before and after medication) and forty-three control subjects completed the tasks under varying sensory conditions. The kinematic measures obtained from the robotic device were used to evaluate SMI. The findings reveal that across all sensory conditions, PD patients had 36% higher endpoint error, 38% higher direction error in reaching tasks, and 43% higher number of violations in tracing tasks than control subjects due to impairment in integrating sensory inputs. However, they still retained motor learning ability and the ability to modulate motor outputs. The medication worsened the SMI deficits as PD patients, after medication, performed worse than before medication when encountering dynamic sensory environments and exhibited impaired motor learning ability.

Background and Purpose: Brain iron dyshomeostasis is increasingly recognized as an important contributor to neurodegeneration. Hereditary hemochromatosis is the most commonly inherited disorder of systemic iron overload. Although there is an increasing interest in excessive brain iron deposition, there is a paucity of evidence showing changes in brain iron exceeding that in healthy controls. Quantitative susceptibility mapping and R2* mapping are established MR imaging techniques that we used to noninvasively quantify brain iron in subjects with hereditary hemochromatosis., Materials and Methods: Fifty-two patients with hereditary hemochromatosis and 47 age- and sex-matched healthy controls were imaged using a multiecho gradient-echo sequence at 3T. Quantitative susceptibility mapping and R2* data were generated, and regions within the deep gray matter were manually segmented. Mean susceptibility and R2* relaxation rates were calculated for each region, and iron content was compared between the groups., Results: We noted elevated iron levels in patients with hereditary hemochromatosis compared with healthy controls using both R2* and QSM methods in the caudate nucleus, putamen, pulvinar thalamus, red nucleus, and dentate nucleus. Additionally, the substantia nigra showed increased susceptibility while the thalamus showed an increased R2* relaxation rate compared with healthy controls, respectively., Conclusions: Both quantitative susceptibility mapping and R2* showed abnormal levels of brain iron in subjects with hereditary hemochromatosis compared with controls. Quantitative susceptibility mapping and R2* can be acquired in a single MR imaging sequence and are complementary in quantifying deep gray matter iron., (© 2022 by American Journal of Neuroradiology.)

Background and Purpose: Hereditary haemochromatosis (HH) is the most common inherited disorder of systemic iron excess in Northern Europeans. Emerging evidence indicates that brain iron overload occurs in HH. Despite this observation, there is a paucity of literature regarding central neurological manifestations, in particular movement disorders, in HH. The current study documents deep gray matter (DGM) nuclei iron deposition, movement disorders, and clinicoradiological correlations in HH without liver failure., Methods: This is a cross-sectional study. Consecutive subjects with HFE-haemochromatosis without liver disease were recruited from an outpatient gastroenterology clinic. Age- and sex-matched healthy controls (HCs) were enrolled. Iron content in individual DGM nuclei was measured as mean susceptibility on magnetic resonance imaging using quantitative susceptibility mapping-based regions of interest analysis. Occurrence and phenotype of movement disorders were documented and correlated with patterns of DGM nuclei iron deposition in subjects with HH., Results: Fifty-two subjects with HH and 47 HCs were recruited. High magnetic susceptibility was demonstrated in several DGM nuclei in all HH subjects compared to HCs. Thirty-five subjects with HH had movement disorders. Magnetic susceptibility in specific DGM nuclei correlated with individual movement disorder phenotypes. Serum ferritin, phlebotomy frequency, and duration were poor predictors of brain iron deposition., Conclusions: Abnormal brain iron deposition can be demonstrated on imaging in all subjects with HH without liver failure. A significant proportion of these subjects manifest movement disorders. Peripheral iron measurements appear not to correlate with brain iron deposition. Therefore, routine neurological examination and quantitative brain iron imaging are recommended in all subjects with HH., (© 2022 European Academy of Neurology.)

In this work, we investigate the effect of Parkinson's disease (PD), and common corresponding therapies on vision-based perception of motion, a critical perceptual ability required for performing a wide range of activities of daily livings. While PD has been recognized as mainly a motor disorder, sensory manifestation of PD can also play a major role in the resulting disability. In this paper, for the first time, the effect of disease duration and common therapies on vision-based perception of displacement were investigated. The study is conducted in a movement-independent manner, to reject the shadowing effects and isolate the targeted perceptual disorder to the maximum possible extent. Data was collected using a computerized graphical tool on 37 PD patients [6 early-stage de novo , 25 mid-stage using levodopa therapy, six later-stage using deep brain stimulation (DBS)] and 15 control participants. Besides the absolute measurement of perception through a psychometric analysis on two tested position reference magnitudes, we also investigated the linearity in perception using Weber's fraction. The results showed that individuals with PD displayed significant perceptual impairments compared to controls, though early-stage patients were not impaired. Mid-stage patients displayed impairments at the greater of the two tested reference magnitudes, while late-stage patients were impaired at both reference magnitudes. Levodopa and DBS use did not cause statistically significant differences in absolute displacement perception. The findings suggest abnormal visual processing in PD increasing with disease development, perhaps contributing to sensory-based impairments of PD such as bradykinesia, visuospatial deficits, and abnormal object recognition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bernardinis, Atashzar, Patel and Jog.)

Pathological hand tremor (PHT) is a common symptom of Parkinson's disease (PD) and essential tremor (ET), which affects manual targeting, motor coordination, and movement kinetics. Effective treatment and management of the symptoms relies on the correct and in-time diagnosis of the affected individuals, where the characteristics of PHT serve as an imperative metric for this purpose. Due to the overlapping features of the corresponding symptoms, however, a high level of expertise and specialized diagnostic methodologies are required to correctly distinguish PD from ET. In this work, we propose the data-driven [Formula: see text] model, which processes the kinematics of the hand in the affected individuals and classifies the patients into PD or ET. [Formula: see text] is trained over 90 hours of hand motion signals consisting of 250 tremor assessments from 81 patients, recorded at the London Movement Disorders Centre, ON, Canada. The [Formula: see text] outperforms its state-of-the-art counterparts achieving exceptional differential diagnosis accuracy of [Formula: see text]. In addition, using the explainability and interpretability measures for machine learning models, clinically viable and statistically significant insights on how the data-driven model discriminates between the two groups of patients are achieved.

Recent clinical trials of transcranial direct current stimulation (tDCS) in depression have shown contrasting results. Consequently, we used in-vivo neuroimaging to confirm targeting and modulation of depression-relevant neural circuitry by tDCS. Depressed participants (N = 66, Baseline Hamilton Depression Rating Scale (HDRS) 17-item scores ≥14 and <24) were randomized into Active/Sham and High-definition (HD)/Conventional (Conv) tDCS groups using a double-blind, parallel design, and received tDCS individually targeted at the left dorsolateral prefrontal cortex (DLPFC). In accordance with Ampere's Law, tDCS currents were hypothesized to induce magnetic fields at the stimulation-target, measured in real-time using dual-echo echo-planar-imaging (DE-EPI) MRI. Additionally, the tDCS treatment trial (consisting of 12 daily 20-min sessions) was hypothesized to induce cerebral blood flow (CBF) changes post-treatment at the DLPFC target and in the reciprocally connected anterior cingulate cortex (ACC), measured using pseudo-continuous arterial spin labeling (pCASL) MRI. Significant tDCS current-induced magnetic fields were observed at the left DLPFC target for both active stimulation montages (Brodmann's area (BA) 46: p HD  = 0.048, Cohen's d HD  = 0.73; p Conv  = 0.018, d Conv  = 0.86; BA 9: p HD  = 0.011, d HD  = 0.92; p Conv  = 0.022, d Conv  = 0.83). Significant longitudinal CBF increases were observed (a) at the left DLPFC stimulation-target for both active montages (p HD  = 3.5E-3, d HD  = 0.98; p Conv  = 2.8E-3, d Conv  = 1.08), and (b) at ACC for the HD-montage only (p HD  = 2.4E-3, d HD  = 1.06; p Conv  = 0.075, d Conv  = 0.64). These results confirm that tDCS-treatment (a) engages the stimulation-target, and (b) modulates depression-relevant neural circuitry in depressed participants, with stronger network-modulations induced by the HD-montage. Although not primary outcomes, active HD-tDCS showed significant improvements of anhedonia relative to sham, though HDRS scores did not differ significantly between montages post-treatment.

Vertical current steering (vCS) divides current between multiple contacts, which reduces radial spread to fine-tune the electric field shape and improves neuroanatomical targeting. vCS may improve the variable responsiveness of Parkinsonian gait to conventional deep brain stimulation. We hypothesized that vCS elicits greater improvement in ambulation in Parkinson's disease patients compared to conventional, single-contact stimulation. vCS was implemented with divisions of 70%/30% and 50%/50% and compared to single-contact stimulation with four therapeutic window amplitudes in current-controlled systems. Walking at a self-selected pace was evaluated in seven levodopa-responsive patients. Integrative measures of gait and stimulation parameters were assessed with the functional ambulation performance (FAP) score and total electrical energy delivered (TEED), respectively. A two-tailed Wilcoxon matched-pairs signed rank test assessed the effect of each stimulation condition on FAP and TEED and compared regression slopes; further, a two-tailed Spearman test identified correlations. vCS significantly lowered the TEED (P < 0.0001); however, FAP scores were not different between conditions (P = 0.786). Compared to single-contact stimulation, vCS elicited higher FAP scores with lower TEED (P = 0.031). FAP and TEED were positively correlated in vCS (P = 2.000 × 10 -5 , r = 0.397) and single-contact stimulation (P = 0.034, r = 0.205). Therefore, vCS and single-contact stimulation improved ambulation similarly but vCS reduced the TEED and side-effects at higher amplitudes.

The global aging phenomenon has increased the number of individuals with age-related neurological movement disorders including Parkinson's Disease (PD) and Essential Tremor (ET). Pathological Hand Tremor (PHT), which is considered among the most common motor symptoms of such disorders, can severely affect patients' independence and quality of life. To develop advanced rehabilitation and assistive technologies, accurate estimation/prediction of nonstationary PHT is critical, however, the required level of accuracy has not yet been achieved. The lack of sizable datasets and generalizable modeling techniques that can fully represent the spectrotemporal characteristics of PHT have been a critical bottleneck in attaining this goal. This paper addresses this unmet need through establishing a deep recurrent model to predict and eliminate the PHT component of hand motion. More specifically, we propose a machine learning-based, assumption-free, and real-time PHT elimination framework, the PHTNet, by incorporating deep bidirectional recurrent neural networks. The PHTNet is developed over a hand motion dataset of 81 ET and PD patients collected systematically in a movement disorders clinic over 3 years. The PHTNet is the first intelligent systems model developed on this scale for PHT elimination that maximizes the resolution of estimation and allows for prediction of future and upcoming sub-movements.

A new approach is presented for localizing the Subthalamic Nucleus (STN) during Deep Brain Stimulation (DBS) surgery based on microelectrode recordings (MERs). DBS is an accepted treatment for individuals living with Parkinson's Disease (PD). This surgery involves implantation of a permanent electrode inside the STN to deliver electrical current. Since the STN is a very small region inside the brain, accurate placement of an electrode is a challenging task for the surgical team. Prior to placement of the permanent electrode, microelectrode recordings of brain activity are used intraoperatively to localize the STN. The placement of the electrode and the success of the therapy depend on this location. In this paper, an objective approach is implemented to help the surgical team in localizing the STN. This is achieved by processing the MER signals and extracting features during the surgery to be used in a Machine Learning (ML) algorithm for defining the neurophysiological borders of the STN. For this purpose, a new classification approach is proposed with the goal of detecting both the dorsal and the ventral borders of the STN during the surgical procedure. Results collected from 100 PD patients in this study, show that by calculating and extracting wavelet transformation features from MER signals and using a data-driven computational deep neural network model, it is possible to detect the borders of the STN with an accuracy of 92%. The proposed method can be implemented in real-time during the surgery to model the neurophysiological nonlinearity along the path of the electrode trajectory during insertion.

Non-motor symptoms in Parkinson's Disease (PD) predate motor symptoms and substantially decrease quality of life; however, detection, monitoring, and treatments are unavailable for many of these symptoms. Temporal perception abnormalities in PD are generally attributed to altered Basal Ganglia (BG) function. Present studies are confounded by motor control facilitating movements that are integrated into protocols assessing temporal perception. There is uncertainty regarding the BG's influence on timing processes of different time scales and how PD therapies affect this perception. In this study, PD patients using Levodopa (n = 25), Deep Brain Stimulation (DBS; n = 6), de novo patients (n = 6), and healthy controls (n = 17) completed a visual temporal perception task in seconds and sub-section timing scales using a computer-generated graphical tool. For all patient groups, there were no impairments seen at the smaller tested magnitudes (using sub-second timing). However, all PD groups displayed significant impairments at the larger tested magnitudes (using interval timing). Neither Levodopa nor DBS therapy led to significant improvements in timing abilities. Levodopa resulted in a strong trend towards impairing timing processes and caused a deterioration in perceptual coherency according to Weber's Law. It is shown that timing abnormalities in PD occur in the seconds range but do not extend to the sub-second range. Furthermore, observed timing deficits were shown to not be solely caused by motor deficiency. This provides evidence to support internal clock models involving the BG (among other neural regions) in interval timing, and cerebellar control of sub-second timing. This study also revealed significant temporal perception deficits in recently diagnosed PD patients; thus, temporal perception abnormalities might act as an early disease marker, with the graphical tool showing potential for disease monitoring.

Parkinson's disease is associated with hyperactivity of the subthalamic nucleus (STN), contributing to motor and gait disturbances. Although deep brain stimulation of the STN alleviates certain motor dysfunction, its specific effect on gait abnormalities remains controversial. This study investigated the long-term changes in locomotion following direct infusions of botulinum toxin-A into the globus pallidus internal segment (GPi) to suppress the flow of information from the STN to the GPi in a hemiparkinsonian rat model. Static and dynamic gait parameters were quantified using a CatWalk apparatus. Interestingly, botulinum toxin-A at 0.5 ng significantly reduced only the dynamic gait parameters of hemiparkinsonian rats at 1 week and 1 month post-infusion, while static gait parameters did not change. This study offers new insights into the complexity of basal ganglia in locomotor control and shows the potential of central infusion of botulinum toxin-A as a novel intervention in the study of experimental hemiparkinson's disease., Competing Interests: We have the following interests: This study was partially funded by an unrestricted grant from Merz Pharmaceuticals. The funding agency had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study. There are no patents, further products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Aim: Modulation of electrical activity in the subthalamic nucleus has been therapeutically effective in Parkinson's disease. Pharmacological manipulation of glutamate release from subthalamic neurons could also favourably alter basal ganglia activity to improve motor symptoms. This study investigates the efficacy of selective suppression of hyperactive glutamatergic input from the subthalamic nucleus to the globus pallidus internal segment by botulinum toxin A (BoNT-A) in a parkinsonian model., Methods: Unilateral 6-hydroxydopamine lesioned parkinsonian rodents and controls received microinfusions of BoNT-A or vehicle into the ipsilateral internal globus pallidus (n = 8 per group). Changes in gait were measured by the CatWalk apparatus, along with assessment of apomorphine-induced rotational behaviour prior to and following BoNT-A injection. Immunofluorescent staining for markers of glutamatergic, GABAergic and total terminals was performed at the internal globus pallidus., Results: Administration of a single dose of BoNT-A (0.5 ng) significantly improved the rotational asymmetry and gait abnormalities. Ameliorations in speed, body speed variation, cadence and walking pattern were comparable to pre-lesioned animals, and persisted up to 1 month following BoNT-A injection. These changes are associated to BoNT-A's ability to selectively target glutamatergic terminals., Conclusion: Blockade of subthalamic hyperactivity by BoNT-A leads to sufficient reorganization in the basal ganglia needed to generate a consistent rhythmic pattern of walking. This suggests the potential use of intracerebral BoNT-A to produce effective neuromodulation in the parkinsonian brain, as well as expansion into other neurodegenerative disorders linked to excitotoxity., (© 2018 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: Parkinson disease (PD) patients have turning impairments that may increase fall risk. Clinics lack specialized kinematic equipment used in gait and turn analysis and require a simple method to evaluate fall risk and advise patients in turning strategy selection., Objectives: To enhance understanding of PD turning strategies and determine if turning can be assessed using a video-recording and categorization method, we compared 180-degree and 90-degree turns as a function of medication status and dual-tasking (DT)., Methods: 21 PD participants (H&Y stage 1-3) in PD-ON and PD-OFF medication states and 16 controls completed 180-degree and 90-degree turn-tasks with and without DT. Video-recordings of tasks permitted classification of 180-degree turns into Few-Step turns (FST) vs. Multi-Step turns (MST) and 90-degree turns into Step vs. Spin-turns. FST were further sub-classified into Twisting vs. Sideways turns and MST into Backward, Festination, Forward or Wheeling turns. Percentages of subtypes were analyzed across groups by task., Results: IN 180-degree tasks, there was an effect of group: FST vs. MST F(2,55) = 9.578, p < .001. PD participants in the off-medication state (PD-OFF) produced significantly more MST with a larger number of different turning subtypes vs. controls or PD on medication (PD-ON). In 90-degree tasks, controls significantly increased their proportion of Step-turns while DT (p < .001), an adaptation not observed in PD-ON or PD-OFF., Conclusions: PD turning impairments may stem from an inability to select a unified turning strategy and to adapt to the turning environment, which may be exacerbated in PD-OFF. Video-analysis may prove beneficial in predicting a clinical course for PD patients by revealing features of turning dysfunction., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Botulinum neurotoxins (BoNTs) produce local chemo-denervation by cleaving soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins. Botulinum neurotoxins are therapeutically indicated in several neurological disorders and have been in use for three decades. The long-term efficacy, safety, and side effects of BoNTs have been well documented in the literature. However, the development of muscle atrophy following chronic exposure to BoNTs has not received sufficient attention. Muscle atrophy is not only cosmetically distressing, but also has an impact on future injections. An extensive literature search was conducted on atrophy and mechanisms of atrophy. Five hundred and four relevant articles in the English language were reviewed. This review revealed the surprising lack of documentation of atrophy within the literature. In addition, as demonstrated in this review, the mechanisms and the clinical factors that may lead to atrophy have also been poorly studied. However, even with this limited information it is possible to indicate factors that could modify the clinical approach to botulinum toxin injections. This review highlights the need for further study of atrophy following BoNT injections.

Corticobasal syndrome is a rare neurodegenerative disorder, which presents with a progressive, asymmetrical, akinetic rigid syndrome and early cortical signs. However, clinical, pathological, and electrophysiological heterogeneity makes the understanding of this syndrome challenging. Corticobasal syndrome can have various pathological substrates including corticobasal degeneration, Alzheimer's disease, Fronto-temporal degeneration with TDP inclusions, Creutzfeldt-Jakob disease, and progressive supranuclear palsy (PSP). Furthermore, tools such as transcranial magnetic stimulation (TMS) and functional neuroimaging techniques like PET and SPECT have not been adequately used to supplement the clinico-pathological heterogeneity. TMS studies in CBS have revealed changes in cortical excitability and transcortical inhibition. Despite the availability of more than 2 decades, its potential in CBS has not been fully utilized in studying the cortical plasticity and effect of Levodopa on central neurophysiology. PET and SPECT studies in CBS have shown abnormalities in regional glucose metabolism, asymmetrical involvement of presynaptic dopaminergic system, and ascending cholinergic connections to the cortex. While most studies have shown normal D2 receptor-binding activity in striatum of CBS cases, the results have not been unanimous. Functional neuroimaging and TMS studies in CBS have shown the involvement of GABAergic, muscarinic, and dopaminergic systems. In this review, we aim to provide the current state of understanding of central neurophysiology and neurochemistry of CBS using TMS and functional neuroimaging techniques. We also highlight the heterogeneous nature of this disorder and the existing knowledge gaps.

Objective: Multiple system atrophy (MSA) is an incurable neurodegenerative illness in which progressive symptoms, including stridor and acute laryngeal obstruction, occur. Advanced care planning and palliative care discussions in people living with MSA are not well defined. The aim of the present study is to evaluate advanced care planning and current practices in palliative care in MSA to identify opportunities for improving quality of care., Methods: The study is a retrospective chart review assessing the focus and timing of palliative care discussions in people living with MSA. Some 22 charts were reviewed., Results: A total of 22 patients were included. The most common symptoms were parkinsonism, orthostatic hypotension, GI/GU dysfunction, ataxia and gait impairment. Six patients had stridor. Of the palliative care discussions that took place, the most common topics were diagnosis, symptoms or symptom management, and prognosis. In the majority of patients who died and who had a do-not-attempt-resuscitation order, discussions surrounding resuscitation and goals of care took place only hours before death., Conclusions: There is no standard approach to advanced care planning and palliative care discussions in people living with MSA. We propose a framework to guide advanced care planning and palliative care discussions in MSA.

Competing Interests: Mandar Jog reports honoraria from Merz Pharmaceuticals, Allergan and AbbVie; and grants from the Canadian Institutes of Health Research, Academic Medical Organization of Southwestern Ontario, Lawson Health Research Institute, AGE-WELL Networks of Centres of Excellence, Merz Pharmaceuticals and Boston Scientific. He occasionally serves on advisory boards of Allergan, Boston Scientific, AbbVie and Merz Pharmaceuticals. No other competing interests were declared.

Abnormality of sensorimotor integration in the basal ganglia and cortex has been reported in the literature for patients with task-specific focal hand dystonia (FHD). In this study, we investigate the effect of manipulation of kinesthetic input in people living with writer's cramp disorder (a major form of FHD). For this purpose, severity of dystonia is studied for 11 participants while the symptoms of seven participants have been tracked during five sessions of assessment and Botulinum toxin injection (BoNT-A) therapy (one of the current suggested therapies for dystonia). BoNT-A therapy is delivered in the first and the third session. The goal is to analyze the effect of haptic manipulation as a potential assistive technique during BoNT-A therapy. The trial includes writing, hovering, and spiral/sinusoidal drawing subtasks. In each session, the subtasks are repeated twice when (a) a participant uses a normal pen, and (b) when the participant uses a robotics-assisted system (supporting the pen) which provides a compliant virtual writing surface and manipulates the kinesthetic sensory input. The results show (p-value using one-sample t-tests) that reducing the writing surface rigidity significantly decreases the severity of dystonia and results in better control of grip pressure (an indicator of dystonic cramping). It is also shown that (p-value based on paired-samples t-test) using the proposed haptic manipulation strategy, it is possible to augment the effectiveness of BoNT-A therapy. The outcome of this study is then used in the design of an actuated pen as a writing-assistance tool that can provide compliant haptic interaction during writing for FHD patients.

The striatum and the subthalamic nucleus (STN) are two separate input structures into the basal ganglia (BG). Accordingly, research to date has primarily focused on the distinct roles of these structures in motor control and cognition, often through investigation of Parkinson's disease (PD). Both structures are divided into sensorimotor, associative, and limbic subdivisions based on cortical connectivity. The more recent discovery of the STN as an input structure into the BG drives comparison of these two structures and their respective roles in cognition and motor control. This review compares the role of the striatum and STN in motor response inhibition and execution, competing motor programs, feedback based learning, and response planning. Through comparison, it is found that the striatum and STN have highly independent roles in motor control but also collaborate in order to execute desired actions. There is also the possibility that inhibition or activation of one of these structures indirectly contributes to the function of other connected anatomical structures. Both structures contribute to selective motor response inhibition, which forms the basis of many tasks, but the STN additionally contributes to global inhibition through the hyperdirect pathway. Research is warranted on the functional connectivity of the network for inhibition involving the rIFG, preSMA, striatum, and STN.

Existing quality-of-life instruments for Parkinson's disease (PD) may not fully assess quality of life (QoL) for people with PD in a holistic and multidimensional manner. This study examines the subscale structure, validity, and internal-consistency reliability of the McGill Quality of Life (MQoL) Questionnaire in a sample of people with PD. This cross-sectional study evaluates the MQoL-PD by using Cronbach's alpha and principal components analysis. A total of 81 consenting people with PD from a tertiary care outpatient clinic were studied. Scores were tabulated for the motor Unified Parkinson's Disease Rating Scale (mUPDRS), the Short Form Health Survey (SF-36), the Parkinson's Disease Questionnaire (PDQ-39), the MQoL Single-Item Scale (MQoL-SIS), and the MQoL Questionnaire (MQoL). Cronbach's alpha for the MQoL-PD was: physical symptoms, 0.83; psychological symptoms, 0.59; and existential/support symptoms, 0.76. Important contributors to QoL in PD include mobility, bowel and bladder function, fatigue, and pain. The MQoL Questionnaire is a valid and reliable measure of physical, psychological, and existential/support symptoms for people with PD.

Background: Management of chronic diseases such as movement disorders can be challenging. Nurse-administered telephone follow-up programs have demonstrated clinical and cost efficacy in a variety of health care models. However, their efficacy in movement disorders has not been sufficiently addressed. This observational study fills a knowledge gap by reporting the nature of individuals utilizing a nurse-administered telephone service and the reasons for and the outcomes of calls., Method: Consecutive calls received by the clinic for a 12-month duration were recorded. A sample of 312 calls from 132 patient charts was analyzed. Variables for analysis and coding schema were determined a-priori and included demographic information as well as information around the reasons for and outcomes of calls. The narratives of documented calls were reviewed retrospectively and responses coded for analysis by a separate researcher. Data was analyzed using descriptive statistical methods., Result: Patients made the majority of calls (49%). 27% of calls related to worsening symptoms and another 35% of calls related to medication issues or renewals. The mean call duration was 15.93 minutes. The majority of calls were received mid-way between clinic visits (M = 89.24 days). The nurse resolved 84% of calls independently. The mean number of calls per patient was 2.93. Issues reported by patients were resolved (approximately 90%) without need for follow-up emergency, family, or subspecialty clinic visits., Conclusion: The results underscore the complexity of medical issues in a movement disorders population. The current study provides support for a nurse-administered telephone follow-up program in movement disorders.

Chronic administration of levodopa, while producing an "awakening" in patients with Parkinson disease (PD), causes disabling side effects such as motor fluctuations and dyskinesia. Indeed the most common reason for deep brain stimulation (DBS) in patients with PD is for treating these complications. However, our understanding of the complexities of these complications is still in the early days. Animal models (primate and rodent) have been exceedingly helpful in elucidating some of the mechanisms. More work needs to be done. In the paper by Gilmour et al. (2011) the authors have investigated the neuronal firing properties and local field potentials of two basal ganglia structures, in response to chronic treatment, to tackle this very question. This commentary attempts to place the work in the context of PD animal models, electrophysiology and where we need to go., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Previous research has shown that skill focused attention may be beneficial for the performance of complicated motor tasks in individuals with Parkinson's disease (PD). The objective of this study was to assess the impact of skill focused attention instructions on gait under temporal movement constraints that may reflect common challenges experienced in daily life. Eighteen patients with PD walked a straight pathway under two different attention focus conditions (no instruction, skill focused instruction) and two different walking speeds (preferred pace, as fast as possible). In the no instruction condition, patients were not told "where" attention should be directed. In the skill focused instruction condition, patients were told to focus on the foot contacting the floor with each step. Spatial and temporal gait measures, as well as, trunk sway were used to quantify walking performance. The results showed that when walking at a preferred pace, skill focused instructions benefited gait performance (e.g., increased gait velocity, larger steps, more trunk sway). However, when walking as fast as possible, skill focused instructions had the opposite effect on gait performance (e.g., decreased gait velocity, smaller steps, and less trunk sway). This study demonstrates that skill focused instructions may contribute to the prioritization of stability under imposed temporal movement constraints. Clinicians should be aware of the processes involved in prioritization of movement components versus task goals in PD and the potential application of an attention based instructional set in altering priorities in this population., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Lingual movement disorders are a rare but serious manifestation of neurologic disease, which have the potential to cause significant morbidity. Traditionally, these disorders were treated with pharmacotherapy achieving only limited results. Several case series have demonstrated the effectiveness of Botulinum toxin injection for the management of focal lingual movement disorders; however, apprehension persists regarding intralingual injections due to the risk of dysphagia. Here, we report seven patients with lingual movement disorders treated with intralingual Botox (Allergan product) injections via a novel superior approach into the genioglossus over a period of 3 to 72 months. All patients experienced a marked improvement in their abnormal tongue movements with no substantial bleeding or dysphagia. Lingual Botulinum toxin injection should be considered a safe and viable treatment option for a variety of disorders affecting the tongue.

This review assesses the current opinion towards early palliative care in neurology and discusses the existing evidence base. A comprehensive literature search resulted in 714 publications with 53 being directly relevant to the scope of this review. The current literature reflects primarily expert opinion and describes a growing interest in the early introduction of palliative principles into neurological care. Early initiation of palliative interventions has the potential to improve quality of life, enhance symptom management and assist in advance care planning. Further data is required to determine whether this shift in philosophy has a positive impact on patient care.

Objective: The purpose of this study was to determine whether tasks involving effortful attention would cause augmentation of rigidity in patients with mild Parkinson disease., Methods: In 17 subjects with mild Parkinson disease, rigidity in a single arm was assessed during various experimental conditions by a blinded movement disorders neurologist. Rigidity was scored separately at the wrist and the elbow using an ordinal scale. In three of the conditions, sustained attention was directed toward visual, auditory or movement-related stimuli. Two varieties of Froment maneuver served as positive controls: contralateral hand opening-closing or ipsilateral foot tapping. In addition, rigidity was assessed twice with subjects resting. The examiner was unaware of the sequence of experimental conditions and this was changed for each subject. Mean rigidity scores for the various experimental conditions were compared against the baseline state (an average of both trials with the patient resting) using a repeated measures ANOVA and post-hoc Tukey-Kramer multiple comparisons test., Results: Rigidity was significantly increased from baseline with each of the attentional tasks (p < 0.01 to p < 0.001) and also with the two Froment maneuvers (p < 0.001). Rigidity augmentation with contralateral hand opening-closing was significantly greater than with any of the attentional tasks (p < 0.05 to p < 0.001)., Conclusion: Tasks of effortful attention did appear to augment rigidity in patients with mild Parkinson disease. We speculate that the greater augmentation seen with the Froment maneuver could have an anatomic basis.

Our goal was to determine whether bradykinesia is present in choreic adult-onset Huntington's disease (HD) patients, and determine the impact of chorea on their voluntary movements. We recorded whole-body involuntary movements (WBIM) and voluntary motor acts simultaneously, using a magnetic tracker system, in 15 choreic HD patients and 15 healthy age- and gender-matched control subjects. Participants were asked to perform two distinct tasks; a manual-tracking (MT) task yielding a measure of chorea intrusion during accurate movements, and a rapid alternating movement (RAM) task, yielding measures of bradykinesia. Results show that patients with HD presented with deviations from the target that hindered their ability to match the target velocity during the MT task. Furthermore, error in performance was correlated with the amplitude of whole-body chorea (Rho=0.67), illustrating the deleterious effect of chorea during accurate movements. However, patients with choreic HD presented with significantly higher RAM range and velocity than matched controls, therefore ruling out the idea that bradykinesia is a systematic feature of HD even when chorea is predominant. The present results imply that patients may have benefited from an intact direct pathway ("select ON" pathway in the focused attention model of basal ganglia function) that allowed them to supersede any dysfunctions associated with the progressive alteration of the "control function" (striatal-globus pallidus-subthalamic) pathway responsible for generating the chorea. Finally, the present results suggest that patients with adult-onset HD having chorea would greatly benefit from improved treatments aiming at reducing their involuntary movements while maintaining proper motor function.

Objectives: Clinical observations have noted variability in amplitude of levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) and chorea in Huntington's disease (HD) during the day. However, no studies have examined whether both the amplitude and body location (motor topography) of whole-body involuntary movement (WBIM) varied over short periods of time (seconds or minutes), which may have a distinct and significant effect on how disruptive these WBIM may be. The present study quantified the variability of WBIM amplitude and motor topography in patients with PD having LID and in patients with HD having chorea., Patients and Methods: WBIM was quantified using the MotionMonitor magnetic motion tracker system. Five patients in each group were tested in two conditions: sitting and standing., Results: WBIM increased from sitting to standing, more so in choreic patients. WBIM varied from 17% to 102% of total WBIM amplitude. Chorea tended to present with greater variability than LID in absolute terms in the standing condition, but not when the mean WBIM amplitude was taken into consideration. Motor topography of WBIM also varied more in the HD group, but mostly in the seated condition where more limbs were free to move. Neither group expressed any laterality of involuntary movement, with amplitude being equally distributed on both sides of the body., Conclusion: Results show significant short-term variability in amplitude of chorea and LID, as well as, variability in location of these involuntary movements, illustrating the complexity of the adaptations required to live and be active with involuntary movements such as HD chorea or PD dyskinesias.

Fatigue is a common nonmotor symptom in idiopathic Parkinson disease (IPD) that can prominently affect everyday function. This study was a randomized, double-blind, placebo-controlled trial evaluating methylphenidate for the treatment of fatigue in patients with IPD maintained on their regular medications. Thirty-six patients were randomized to receive either methylphenidate (10 mg three times per day; n = 17) or placebo (n = 19) for 6 weeks. Primary outcomes were the change from baseline on two separate self-report fatigue questionnaires: the Fatigue Severity Scale (FSS) and the Multidimensional Fatigue Inventory (MFI). Secondary outcomes included the Unified Parkinson Disease Rating Scale (UPDRS) motor score and the five individual domains of the MFI. Fourteen patients in the methylphenidate group and 16 patients in the control group remained on the intervention for the entire study period. In the treatment arm, mean FSS score was reduced by 6.5 points (from a baseline of 43.8) and mean MFI score was reduced by 8.4 points (from a baseline of 51.0). Both these reductions were significant (P < 0.04). Smaller reductions in the placebo group were nonsignificant. Mean UPDRS motor score did not change significantly in either group. Analysis of MFI subscores showed a significant reduction in General Fatigue in the methylphenidate group (P < 0.001). Overall, adverse effects of medication were more frequent in the placebo group. In conclusion, methylphenidate was effective in lowering fatigue scores in patients with IPD following a 6-week treatment period., ((c) 2007 Movement Disorder Society.)

The basal ganglia have been implicated in timing control, yet the nature of timing disturbances in Parkinson's disease (PD) is poorly understood. We evaluated the influence of timing cues on spatiotemporal aspects of gait control and its variability, and the impact of dopaminergic treatment on timing. Three separate groups: 19 PD (OFF state); 24 PD (ON state); and 30 control participants were tested. Participants walked on a computerized carpet at four randomized and metronome-controlled rates: self-paced, 60, 80, or 100 steps/min. To our knowledge, this is the first study to demonstrate that medicated PD patients had poorer timing control than patients withdrawn from medication and healthy participants when modulating timing to an external stimulus. Increased step-to-step timing variability and deficits in mean temporal gait characteristics revealed that the medicated PD group (in contrast to nonmedicated PD group) performed least like healthy participants. This was observable in externally-cued conditions, but not during self-paced gait. Similar to previous research, step length contributed to overall slowness in PD, while temporal characteristics of gait did not. Interestingly, healthy participants increased stride length with each increase in cue rate, whereas both PD groups locked their step length regardless of temporal demand. Step-to-step variability differences between PD and healthy (e.g. step and double-support time measurements) may be indicative of specific basal ganglia involvement in temporal control of gait., ((c) 2007 Movement Disorder Society.)

Recent studies suggest that, for many adult-onset neurological diseases, persons born at a certain time of year are at higher risk of the disease. Small-scale studies have suggested that persons born in the spring may be at higher risk of developing Parkinson's disease (PD) late in life. There have also been suggestions that there are clusters of PD birth dates in the years of major influenza pandemics. To determine whether there is any seasonal variation in the birth dates of PD patients, we examined birth dates of 8,168 PD patients collected from subspecialty movement disorder clinics across Canada. Patterns of seasonality of birth were examined and compared with the general Canadian population. In addition, we compared counts of patients born in the years of major influenza pandemics with the number born in the surrounding years. We found no evidence of systematic seasonal variation in PD incidence by birth date, or of clustering of birth dates during influenza pandemic years in PD patients.

Learning is important for humans and can be disrupted by disease. However, the essence of how learning may be represented within a neuronal network is still elusive. Spike trains generated by neurons have been demonstrated to carry information which is relevant for learning. The present study uses well-established mutual information (MI) analysis techniques to better understand learning within neuronal ensembles. Spike trains in tetrode recordings from the dorso-lateral striatum were used for computing MI as rats learnt a T-maze procedural task. We demonstrate that in in-vivo recordings the growth of MI is reflected in the behavioral response as learning proceeds. These changes in MI are seen to correspond to three phases, a low MI value, namely early learning, a rapid increase in MI value, task-acquisition and stabilization of MI, over-training. Over multiple training sessions, small changes in MI within the neuronal network suddenly produce a big change in ensemble MI during the task acquisition phase. This phase represents the "tipping point" in the neuronal network where the MI growth builds habits during motor learning in the striatum.

This paper presents a new technique for analyzing the recorded information from tetrodes in freely behaving rats, based on independent component analysis (ICA). The ion-specific pumps and channels allow fast transfer of charges such as Na+, K+, Cl- and eventually Ca2+ during each action potential (AP). These groups of charges under an electrical field have distinct spatial trajectories. Therefore, the generated signals within a tetrode are considered to be composed mainly by statistically independent signal sources that can be obtained by performing ICA. In order to compute the position of independent sources during AP generation, the triangulation method uses an iterative Newton-Raphson algorithm. The representation of the independent signal sources in three-dimensional tetrode space is then obtained. Since the charge movements are extensively spread on the neuron's surface, the representation in tetrode space reveals electrical spatial patterns of activation during each AP. The analysis of several spikes coming from the same neuron reveals small changes from spike to spike in the 3D shape. Since information within spikes is highly transferred by ionic fluxes these electrical patterns of activation reflect neuronal computation occurring during each AP.

The ability of neurons to generate electrical signals is strongly dependent on the evolution of ion-specific pumps and channels that allow the transfer of charges under the influence of electric fields and concentration gradients. This paper presents a novel method by which flow of these charge fluxes may be computed to provide directivity of charge movement. Simulations of charge flow as well as actual electrophysiological data recorded by tetrodes are used to demonstrate the method. The propagation of charge fluxes in space in data from simulation and actual recordings during action potential can be analyzed using signals recorded by tetrodes. Variation in spike directivity can be estimated by computing singular value decomposition of the estimated 3D trajectory data. The analysis of the spike model can be accomplished by performing simulations of presumed equivalent moving charges recorded by the tetrode tips. For in vivo spike recordings, the variation of spike directivity could be obtained using several spikes of selected neurons considering the charge movement model (CMM). The relationship between computer simulation results and tetrode data recordings is examined. The paper concludes by showing that the method for calculating directivity in actual spike recordings is robust. The method allows for improved filtering of data and more importantly may shed light on furthering the study of spatio-temporal encoding in neurons.

The paper presents in detail a method for approximating the spatial position of neural spike activity from tetrode recordings. The method uses a nonlinear mapping of a set of tetrode tip amplitudes into three-dimensional (3D) space, followed by a self-organizing map clustering technique. Viewed as a spike sorting method, it performs better than tetrode peak amplitudes and it is roughly equivalent with amplitude ratios. The technique's appeal to physical location may be of advantage in many investigations.