Differential Responses to Low- and High-Frequency Subthalamic Nucleus Deep Brain Stimulation on Sensor-Measured Components of Bradykinesia in Parkinson's Disease.

INTRODUCTION: The current approach to assessing bradykinesia in Parkinson's Disease relies on the Unified Parkinson's Disease Rating Scale (UPDRS), which is a numeric scale. Inertial sensors offer the ability to probe subcomponents of bradykinesia: motor speed, amplitude, and rhythm. Thus, we sought to investigate the differential effects of high-frequency compared to low-frequency subthalamic nucleus (STN) deep brain stimulation (DBS) on these quantified facets of bradykinesia. METHODS: We recruited advanced Parkinson's Disease subjects with a chronic bilateral subthalamic nucleus (STN) DBS implantation to a single-blind stimulation trial where each combination of medication state (OFF/ON), electrode contacts, and stimulation frequency (60 Hz/180 Hz) was assessed. The Kinesia One sensor system was used to measure upper limb bradykinesia. For each stimulation trial, subjects performed extremity motor tasks. Sensor data were recorded continuously. We identified STN DBS parameters that were associated with improved upper extremity bradykinesia symptoms using a mixed linear regression model. RESULTS: We recruited 22 subjects (6 females) for this study. The 180 Hz STN DBS (compared to the 60 Hz STN DBS) and dopaminergic medications improved all subcomponents of upper extremity bradykinesia (motor speed, amplitude, and rhythm). For the motor rhythm subcomponent of bradykinesia, ventral contacts yielded improved symptom improvement compared to dorsal contacts. CONCLUSION: The differential impact of high- and low-frequency STN DBS on the symptoms of bradykinesia may advise programming for these patients but warrants further investigation. Wearable sensors represent a valuable addition to the armamentarium that furthers our ability to conduct objective, quantitative clinical assessments.

Short-term effects of Pilates-based exercise on upper limb strength and function in people with Parkinson's disease.

BACKGROUND: People with Parkinson's disease (PD) have impaired upper limb motor coordination, limiting the execution of activities of daily living. This study investigated the feasibility and safety of a short-term Pilates-based exercise program in the treatment of upper limb motor coordination for people with PD. METHODS: Fifteen patients - n (%) 4 women/11 men (27/73), median [interquartile range] age 66 [9] years - participated in this quasi-experimental (before-and-after) clinical trial. Patients underwent a 6-week (30 min/day, 3 days/week) Pilates exercise program using Reformer, Cadillac, Chair, and Barrel equipment. Feasibility was evaluated by adherence to the program and the ability to perform the exercises including progressions on difficulty. Safety was evaluated based on self-reported adverse events. Clinical and functional trends before and after the intervention were also computed regarding handgrip strength (HGS), fine motor coordination (9 Hole Peg Test; 9HPT), bradykinesia (Movement Disorder Society - Unified Parkinson's disease Rating Scale; MDS-UPDRS), and upper limb functionality (Test D'évaluation des Membres Supérieurs des Personnes Âgées, TEMPA). RESULTS: Of the 18 Pilates sessions, exercise adherence was 100%. The only adverse event observed was mild muscle pain. Pre-post differences were observed only for body bradykinesia and hypokinesia (1.0 [0.0] vs. 0.0 [1.0] s, adjusted p = 0.048). CONCLUSIONS: A short-term Pilates-based exercise program in the treatment of upper limb muscle strength, manual dexterity, bradykinesia, and functionality is feasible and safe for people with PD. Changes in upper limb bradykinesia encourage randomized clinical trials.

Characterizing Disease Progression in Parkinson's Disease from Videos of the Finger Tapping Test.

INTRODUCTION: Parkinson's disease (PD) is characterized by motor symptoms whose progression is typically assessed using clinical scales, namely the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Despite its reliability, the scale is bounded by a 5-point scale that limits its ability to track subtle changes in disease progression and is prone to subjective interpretations. We aimed to develop an automated system to objectively quantify motor symptoms in PD using Machine Learning (ML) algorithms to analyze videos and capture nuanced features of disease progression. METHODS: We analyzed videos of the Finger Tapping test, a component of the MDS-UPDRS, from 24 healthy controls and 66 PD patients using ML algorithms for hand pose estimation. We computed multiple movement features related to bradykinesia from videos and employed a novel tiered classification approach to predict disease severity that employed different features according to severity. We compared our video-based disease severity prediction approach against other approaches recently introduced in the literature. RESULTS: Traditional kinematics features such as amplitude and velocity changed linearly with disease severity, while other non-traditional features displayed non-linear trends. The proposed disease severity prediction approach demonstrated superior accuracy in detecting PD and distinguishing between different levels of disease severity when compared to existing approaches.

Intra and inter-rater remote assessment of bradykinesia in Parkinson's disease / Evaluación remota de la bradicinesia en la enfermedad de Parkinson mediante análisis intra e inter evaluadores

Introduction: Reliable assessment of individuals with Parkinson's disease (PD) is essential for providing adequate treatment. Clinical assessment is a complex and time-consuming task, especially for bradykinesia, since its evaluation can be influenced by the degree of experience of the examiner, patient collaboration and individual bias. Improvement of the clinical evaluation can be obtained by considering assessments from several professionals. However, this is only true when inter and intra-rater agreement are high. Recently, the Movement Disorder Society highlighted, during the COVID-19 pandemic, the need to develop and validate technologies for remote assessment of the motor status of people with PD. Thus, this study introduces an objective strategy for the remote evaluation of bradykinesia using multi-specialist analysis. Methods: Twelve volunteers with PD participated and these were asked to execute finger tapping, hand opening/closing and pronation/supination movements. Each task was recorded and rated by fourteen PD health experts for each patient. The scores were assessed on an individual basis. Intra and inter-rater agreement and correlation were estimated. Results: The results showed that agreements and correlations between experienced examiners were high with low variability. In addition, group analysis was noted as possessing the potential to solve individual inconsistency bias. Conclusion: Furthermore, this study demonstrated the need for a group with prior training and experience, along with indicating the importance for the development of a clinical protocol that can use telemedicine for the evaluation of individuals with PD, as well as the inclusion of a specialized mediating group. In Addition, this research helps to the development of a valid remote assessment of bradykinesia.(AU)

Introducción: La evaluación confiable de las personas con la enfermedad de Parkinson (EP) es esencial para lograr con un tratamiento adecuado. La evaluación clínica es una tarea compleja y que requiere mucho tiempo, especialmente para la bradicinesia, ya que su evaluación puede verse influenciada por el grado de experiencia del examinador, la colaboración del paciente y el sesgo individual. La mejora de la evaluación clínica se puede obtener considerando las evaluaciones de varios profesionales. Sin embargo, esto solo es más preciso cuando el convenio intra e inter evaluadores es alto. Recientemente, la Sociedad de Trastornos del Movimiento destacó, durante la pandemia COVID-19, la necesidad de desarrollar y validar tecnologías para la evaluación remota del estado motor de las personas con EP. Por lo tanto, este estudio presenta una estrategia objetiva para la evaluación remota de la bradicinesia mediante un análisis multi evaluadores. Métodos: Participaron 12 voluntarios con EP y se les pidió que ejecutaran movimientos de golpeteo de dedos de las manos, movimientos con las manos y pronación-supinación de las manos. Cada ejecución del movimiento fue registrado y calificado por 14 expertos en salud. Las puntuaciones se evaluaron de forma individual. Se estimó el convenio y la correlación intra e inter evaluadores. Resultados: Los resultados mostraron que los convenios y las correlaciones inter evaluadores experimentados son altos con baja variabilidad. Además, se observó que el análisis de grupo posee el potencial de resolver el sesgo de inconsistencia individual. Conclusiones: De esta forma, este estudio demostró la necesidad de un grupo con formación y experiencia previa, señalando la importancia para el desarrollo de un protocolo clínico que utiliza la telemedicina para la evaluación de personas con EP y como la inclusión de un grupo mediador especializado. En realidad, esta investigación propone una evaluación remota eficaz de la bradicinesia.(AU)

Disentangling Bradykinesia and Rigidity in Parkinson's Disease: Evidence from Short- and Long-Term Subthalamic Nucleus Deep Brain Stimulation.

OBJECTIVE: Bradykinesia and rigidity are considered closely related motor signs in Parkinson disease (PD), but recent neurophysiological findings suggest distinct pathophysiological mechanisms. This study aims to examine and compare longitudinal changes in bradykinesia and rigidity in PD patients treated with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: In this retrospective cohort study, the clinical progression of appendicular and axial bradykinesia and rigidity was assessed up to 15 years after STN-DBS in the best treatment conditions (ON medication and ON stimulation). The severity of bradykinesia and rigidity was examined using ad hoc composite scores from specific subitems of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III). Short- and long-term predictors of bradykinesia and rigidity were analyzed through linear regression analysis, considering various preoperative demographic and clinical data, including disease duration and severity, phenotype, motor and cognitive scores (eg, frontal score), and medication. RESULTS: A total of 301 patients were examined before and 1 year after surgery. Among them, 101 and 56 individuals were also evaluated at 10-year and 15-year follow-ups, respectively. Bradykinesia significantly worsened after surgery, especially in appendicular segments (p < 0.001). Conversely, rigidity showed sustained benefit, with unchanged clinical scores compared to preoperative assessment (p > 0.05). Preoperative motor disability (eg, composite scores from the UPDRS-III) predicted short- and long-term outcomes for both bradykinesia and rigidity (p < 0.01). Executive dysfunction was specifically linked to bradykinesia but not to rigidity (p < 0.05). INTERPRETATION: Bradykinesia and rigidity show long-term divergent progression in PD following STN-DBS and are associated with independent clinical factors, supporting the hypothesis of partially distinct pathophysiology. ANN NEUROL 2024;96:234-246.

Deep brain stimulation of symptom-specific networks in Parkinson's disease.

Deep Brain Stimulation can improve tremor, bradykinesia, rigidity, and axial symptoms in patients with Parkinson's disease. Potentially, improving each symptom may require stimulation of different white matter tracts. Here, we study a large cohort of patients (N = 237 from five centers) to identify tracts associated with improvements in each of the four symptom domains. Tremor improvements were associated with stimulation of tracts connected to primary motor cortex and cerebellum. In contrast, axial symptoms are associated with stimulation of tracts connected to the supplementary motor cortex and brainstem. Bradykinesia and rigidity improvements are associated with the stimulation of tracts connected to the supplementary motor and premotor cortices, respectively. We introduce an algorithm that uses these symptom-response tracts to suggest optimal stimulation parameters for DBS based on individual patient's symptom profiles. Application of the algorithm illustrates that our symptom-tract library may bear potential in personalizing stimulation treatment based on the symptoms that are most burdensome in an individual patient.

Hyperkinetic and Hypokinetic Movement Disorders in SSPE: A Systematic Review of Case Reports and Case Series.

Background: Subacute Sclerosing Panencephalitis (SSPE) typically presents with periodic myoclonus; however, a spectrum of movement disorders including dystonia, chorea, tremor, and parkinsonism have also been described. This review aims to evaluate the array of movement disorders in SSPE, correlating them with neuroimaging findings, disease stages, and patient outcomes. Methods: A comprehensive review of published case reports and case series was conducted on patients with SSPE exhibiting movement disorders other than periodic myoclonus. PRISMA guidelines were followed, and the protocol was registered with PROSPERO (2023 CRD42023434650). A comprehensive search of multiple databases yielded 37 reports detailing 39 patients. Dyken's criteria were used for SSPE diagnosis, and the International Movement Disorders Society definitions were applied to categorize movement disorders. Results: The majority of patients were male, with an average age of 13.8 years. Approximately, 80% lacked a reliable vaccination history, and 39% had prior measles infections. Dystonia was the most common movement disorder (49%), followed by parkinsonism and choreoathetosis. Rapid disease progression was noted in 64% of cases, with a disease duration of ≤6 months in 72%. Neuroimaging showed T2/FLAIR MR hyperintensities, primarily periventricular, with 26% affecting the basal ganglia/thalamus. Brain biopsies revealed inflammatory and neurodegenerative changes. Over half of the patients (56%) reached an akinetic mute state or died. Conclusion: SSPE is associated with diverse movement disorders, predominantly hyperkinetic. The prevalence of dystonia suggests basal ganglia dysfunction.

Intra and inter-rater remote assessment of bradykinesia in Parkinson's disease.

INTRODUCTION: Reliable assessment of individuals with Parkinson's disease (PD) is essential for providing adequate treatment. Clinical assessment is a complex and time-consuming task, especially for bradykinesia, since its evaluation can be influenced by the degree of experience of the examiner, patient collaboration and individual bias. Improvement of the clinical evaluation can be obtained by considering assessments from several professionals. However, this is only true when inter and intra-rater agreement are high. Recently, the Movement Disorder Society highlighted, during the COVID-19 pandemic, the need to develop and validate technologies for remote assessment of the motor status of people with PD. Thus, this study introduces an objective strategy for the remote evaluation of bradykinesia using multi-specialist analysis. METHODS: Twelve volunteers with PD participated and these were asked to execute finger tapping, hand opening/closing and pronation/supination movements. Each task was recorded and rated by fourteen PD health experts for each patient. The scores were assessed on an individual basis. Intra and inter-rater agreement and correlation were estimated. RESULTS: The results showed that agreements and correlations between experienced examiners were high with low variability. In addition, group analysis was noted as possessing the potential to solve individual inconsistency bias. CONCLUSION: Furthermore, this study demonstrated the need for a group with prior training and experience, along with indicating the importance for the development of a clinical protocol that can use telemedicine for the evaluation of individuals with PD, as well as the inclusion of a specialized mediating group. In Addition, this research helps to the development of a valid remote assessment of bradykinesia.

Symptom Analysis of Early Parkinson's Disease and its Correlation with High Sensitivity C-reactive Protein.

Parkinson's disease is a debilitating neurodegenerative disease for which there is no cure. It is characterized by bradykinesia, resting tremor, rigidity and postural instability, due to impairment of function of the basal ganglia which is involved in the coordination of body movement. Neuro-inflammation is pathogenesis of development in early Parkinson's disease. High-sensitivity C-reactive protein level is a useful non-specific biochemical marker of inflammation. Objective of this study was to analyze the symptoms of Parkinson disease and it's correlation with high sensitive CRP. Seventy-six Parkinson's disease patients were enrolled in this Cross-sectional observational study that was attended in the Department of Neurology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh from September 2014 to March 2016. Analysis of the symptoms of Parkinson disease and it's correlation with high sensitive CRP were done among these patients. This study was performed on 76 Parkinson disease patients with presented early with symptoms. a positive and highly significant correlation were seen in between duration of tremor and High sensitivity CRP (r=0.430, p<0.001) and between duration of bradykinesia and High sensitivity CRP (r=0.426, p<0.001) which indicate increase duration causes increase level of high-sensitivity C-reactive protein value. The neuro-inflammation plays a significant role in the pathogenesis of symptoms development in early Parkinson's disease.

Time-resolved quantification of fine hand movements as a proxy for evaluating bradykinesia-induced motor dysfunction.

Bradykinesia is a behavioral manifestation that contributes to functional dependencies in later life. However, the current state of bradykinesia indexing primarily relies on subjective, time-averaged categorizations of motor deficits, which often yield poor reliability. Herein, we used time-resolved analyses of accelerometer recordings during standardized movements, data-driven factor analyses, and linear mixed effects models (LMEs) to quantitatively characterize general, task- and therapy-specific indices of motor impairment in people with Parkinson's disease (PwP) currently undergoing treatment for bradykinesia. Our results demonstrate that single-trial, accelerometer-based features of finger-tapping and rotational hand movements were significantly modulated by divergent therapeutic regimens. Further, these features corresponded well to current gold standards for symptom monitoring, with more precise predictive capacities of bradykinesia-specific declines achieved when considering kinematic features from diverse movement types together, rather than in isolation. Herein, we report data-driven, sample-specific kinematic profiles of diverse movement types along a continuous spectrum of motor impairment, which importantly, preserves the temporal scale for which biomechanical fluctuations in motor deficits evolve in humans. Therefore, this approach may prove useful for tracking bradykinesia-induced motor decline in aging populations the future.

Neuronal intranuclear inclusion disease misdiagnosed as Parkinson's disease: a case report.

Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disease that mainly manifests as dementia, muscle weakness, sensory disturbances, and autonomic nervous dysfunction. Herein, we report a 68-year-old Chinese woman who was hospitalized because of resting tremor and bradykinesia that had been present for 7 years. Five years prior, bradykinesia and hypermyotonia had become apparent. She had urinary incontinence and rapid eye movement sleep behavior disorder. She was diagnosed with Parkinson's disease (PD) and received levodopa and pramipexole, which relieved her motor symptoms. During hospitalization, diffusion-weighted imaging revealed a high-intensity signal along the cortical medullary junction. Moreover, a skin biopsy revealed the presence of intranuclear inclusions in adipocytes, fibroblasts, and sweat gland cells. NIID was diagnosed by testing the Notch 2 N-terminal-like C (NOTCH2NLC) gene. We report this case to remind doctors to consider NIID when diagnosing patients with symptoms indicative of Parkinson's disease. Moreover, we note that further research is needed on the mechanism by which levodopa is effective for NIID.

Impaired performance of rapid grip in people with Parkinson's disease and motor segmentation.

Bradykinesia, or slow movement, is a defining symptom of Parkinson's disease (PD), but the underlying neuromechanical deficits that lead to this slowness remain unclear. People with PD often have impaired rates of motor output accompanied by disruptions in neuromuscular excitation, causing abnormal, segmented, force-time curves. Previous investigations using single-joint models indicate that agonist electromyogram (EMG) silent periods cause motor segmentation. It is unknown whether motor segmentation is evident in more anatomically complex and ecologically important tasks, such as handgrip tasks. Aim 1 was to determine how handgrip rates of force change compare between people with PD and healthy young and older adults. Aim 2 was to determine whether motor segmentation is present in handgrip force and EMG measures in people with PD. Subjects performed rapid isometric handgrip pulses to 20-60% of their maximal voluntary contraction force while EMG was collected from the grip flexors and extensors. Dependent variables included the time to 90% peak force, the peak rate of force development, the duration above 90% of peak force, the number of segments in the force-time curve, the number of EMG bursts, time to relaxation from 90% of peak force, and the peak rate of force relaxation. People with PD had longer durations and lower rates of force change than young and older adults. Six of 22 people with PD had motor segmentation. People with PD had more EMG bursts compared to healthy adults and the number of EMG bursts covaried with the number of segments. Thus, control of rapid movement in Parkinson's disease can be studied using isometric handgrip. People with PD have impaired rate control compared to healthy adults and motor segmentation can be studied in handgrip.

Risk factors for hypoactive delirium in patients with nontraumatic ARDS: a prospective observational study.

To investigate the incidence, characteristics and risk factors for hypoactive delirium in patients with nontraumatic acute respiratory distress syndrome (ARDS) and to explore the independent risk factors associated with hypoactive delirium and provide new ideas for early prediction and treatment. Hypoactive delirium is a known serious complication in ARDS patients, and currently, there are no effective early detection models or clinical prediction tools, and there is a lack of clinical treatment. This study included nontraumatic ARDS patients who stayed in the intensive care unit (ICU) for more than 24 h and were older than 18 years. A total of 205 ARDS patients admitted to the ICU of Gansu Provincial People's Hospital between December 2021 and February 2023 were selected. Demographic data, clinical characteristics and laboratory test results were collected within 24 h after the patients entered the ICU. Multivariate logistic regression analysis was used to investigate risk factors, evaluate the clinical prediction effect of the model and construct a nomogram for visual display. The incidence of hypoactive delirium among the patients included in the study was 41%. Patients with hypoactive delirium had hypertension; diabetes mellitus; Acute Physiology and Chronic Health Evaluation II (APACHE II) scores ≥ 15; and increased procalcitonin, C-reactive protein (CRP), lactic dehydrogenase and interleukin-6 (IL-6) levels compared with those without hypoactive delirium. Logistic regression analysis revealed that diabetes mellitus (OR 3.305, 95% CI: 1.866-12.616; p = 0.047), CRP level (OR 1.002, 95% CI: 1.001-1.023; p = 0.044), and IL-6 level (OR 1.045, 95% CI: 1.017-1.063; p = 0.001) were independent risk factors for hypoactive delirium. After receiver operating characteristic (ROC) curve analysis, calibration plot and decision curve analysis (DCA) confirmed that the clinical prediction ability of this study model was satisfactory, and a nomogram was drawn for visual display. Hypoactive delirium is a common serious complication in nontraumatic ARDS patients. Our logistic regression model not only effectively predicts hypoactive delirium early but also reveals potential clinical therapeutic targets.

Functional interaction of abnormal beta and gamma oscillations on bradykinesia in parkinsonian rats.

Bradykinesia, a debilitating symptom characterized by impaired movement initiation and reduced speed in Parkinson's disease (PD), is associated with abnormal oscillatory activity in the motor cortex-basal ganglia circuit. We investigated the interplay between abnormal beta and gamma oscillations in relation to bradykinesia in parkinsonian rats. Our findings showed reduced movement activities in parkinsonian rats, accompanied by enhanced high beta oscillations in the motor cortex, which are closely associated with movement transitional difficulties. Additionally, gamma oscillations correlated with movement velocity in control rats but not in parkinsonian rats. We observed selective coupling between high beta oscillation phase and gamma oscillation amplitude in PD, as well as cortical high beta-broadband gamma phase-amplitude coupling (PAC) negatively influencing locomotor activities in control and PD rats. These findings suggest a collaborative role of cortical beta and gamma oscillations in facilitating movement execution, with beta oscillations being linked to movement initiation and gamma oscillations associated with movement speed. Importantly, the aberrant alterations of these oscillations are closely related to the development of bradykinesia. Furthermore, PAC hold promise as a biomarker for comprehensive assessment of movement performance in PD.

Slowing of Movements in Healthy Aging as a Rational Economic Response to an Elevated Effort Landscape.

Why do we move slower as we grow older? The reward circuits of the brain, which tend to invigorate movements, decline with aging, raising the possibility that reduced vigor is due to the diminishing value that our brain assigns to movements. However, as we grow older, it also becomes more effortful to make movements. Is age-related slowing principally a consequence of increased effort costs from the muscles, or reduced valuation of reward by the brain? Here, we first quantified the cost of reaching via metabolic energy expenditure in human participants (male and female), and found that older adults consumed more energy than the young at a given speed. Thus, movements are objectively more costly for older adults. Next, we observed that when reward increased, older adults, like the young, responded by initiating their movements earlier. Yet, unlike the young, they were unwilling to increase their movement speed. Was their reluctance to reach quicker for rewards due to the increased effort costs, or because they ascribed less value to the movement? Motivated by a mathematical model, we next made the young experience a component of aging by making their movements more effortful. Now the young responded to reward by reacting faster but chose not to increase their movement speed. This suggests that slower movements in older adults are partly driven by an adaptive response to an elevated effort landscape. Moving slower may be a rational economic response the brain is making to mitigate the elevated effort costs that accompany aging.

Objective clinical registration of tremor, bradykinesia, and rigidity during awake stereotactic neurosurgery: a scoping review.

Tremor, bradykinesia, and rigidity are incapacitating motor symptoms that can be suppressed with stereotactic neurosurgical treatment like deep brain stimulation (DBS) and ablative surgery (e.g., thalamotomy, pallidotomy). Traditionally, clinicians rely on clinical rating scales for intraoperative evaluation of these motor symptoms during awake stereotactic neurosurgery. However, these clinical scales have a relatively high inter-rater variability and rely on experienced raters. Therefore, objective registration (e.g., using movement sensors) is a reasonable extension for intraoperative assessment of tremor, bradykinesia, and rigidity. The main goal of this scoping review is to provide an overview of electronic motor measurements during awake stereotactic neurosurgery. The protocol was based on the PRISMA extension for scoping reviews. After a systematic database search (PubMed, Embase, and Web of Science), articles were screened for relevance. Hundred-and-three articles were subject to detailed screening. Key clinical and technical information was extracted. The inclusion criteria encompassed use of electronic motor measurements during stereotactic neurosurgery performed under local anesthesia. Twenty-three articles were included. These studies had various objectives, including correlating sensor-based outcome measures to clinical scores, identifying optimal DBS electrode positions, and translating clinical assessments to objective assessments. The studies were highly heterogeneous in device choice, sensor location, measurement protocol, design, outcome measures, and data analysis. This review shows that intraoperative quantification of motor symptoms is still limited by variable signal analysis techniques and lacking standardized measurement protocols. However, electronic motor measurements can complement visual evaluations and provide objective confirmation of correct placement of the DBS electrode and/or lesioning. On the long term, this might benefit patient outcomes and provide reliable outcome measures in scientific research.

The sound of Parkinson's disease: A model of audible bradykinesia.

INTRODUCTION: Evaluation of bradykinesia is based on five motor tasks from the MDS-UPDRS. Visually scoring these motor tasks is subjective, resulting in significant interrater variability. Recent observations suggest that it may be easier to hear the characteristic features of bradykinesia, such as the decrement in sound intensity or force of repetitive movements. The objective is to evaluate whether audio signals derived during four MDS-UPDRS tasks can be used to detect and grade bradykinesia, using two machine learning models. METHODS: 54 patients with Parkinson's disease and 28 healthy controls were filmed while executing the bradykinesia motor tasks. Several features were extracted from the audio signal, including number of taps, speed, sound intensity, decrement and freezes. For each motor task, two supervised machine learning models were trained, Logistic Regression (LR) and Support Vector Machine (SVM). RESULTS: Both classifiers were able to separate patients from controls reasonably well for the leg agility task, area under the receiver operating characteristic curve (AUC): 0.92 (95%CI: 0.78-0.99) for LR and 0.93 (0.81-1.00) for SVM. Also, models were able to differentiate less severe bradykinesia from severe bradykinesia, particularly for the pronation-supination motor task, with AUC: 0.90 (0.62-1.00) for LR and 0.82 (0.45-0.97) for SVM. CONCLUSION: This audio-based approach discriminates PD from healthy controls with moderate-high accuracy and separated individuals with less severe bradykinesia from those with severe bradykinesia. Sound analysis may contribute to the identification and monitoring of bradykinesia.

Locomotor Behavior and Memory Dysfunction Induced by 3-Nitropropionic Acid in Adult Zebrafish: Modulation of Dopaminergic Signaling.

Huntington's disease (HD) is a progressive neurodegenerative disease characterized by neuropsychiatric disturbance, cognitive impairment, and locomotor dysfunction. In the early stage (chorea) of HD, expression of dopamine D2 receptors (D2R) is reduced, whereas dopamine (DA) levels are increased. Contrary, in the late stage (bradykinesia), DA levels and the expression of D2R and dopamine D1 receptors (D1R) are reduced. 3-Nitropropionic acid (3-NPA) is a toxin that may replicate HD behavioral phenotypes and biochemical aspects. This study assessed the neurotransmitter levels, dopamine receptor gene expression, and the effect of acute exposure to quinpirole (D2R agonist) and eticlopride (D2R antagonist) in an HD model induced by 3-NPA in adult zebrafish. Quinpirole and eticlopride were acutely applied by i.p. injection in adult zebrafish after chronic treatment of 3-NPA (60 mg/kg). 3-NPA treatment caused a reduction in DA, glutamate, and serotonin levels. Quinpirole reversed the bradykinesia and memory loss induced by 3-NPA. Together, these data showed that 3-NPA acts on the dopaminergic system and causes biochemical alterations similar to late-stage HD. These data reinforce the hypothesis that DA levels are linked with locomotor and memory deficits. Thus, these findings may suggest that the use of DA agonists could be a pharmacological strategy to improve the bradykinesia and memory deficits in the late-stage HD.

Ucp4 Knockdown of Cerebellar Purkinje Cells Induces Bradykinesia.

Although uncoupling protein 4 (UCP4) is the most abundant protein reported in the brain, the biological function of UCP4 in cerebellum and pathological outcome of UCP4 deficiency in cerebellum remain obscure. To evaluate the role of Ucp4 in the cerebellar Purkinje cells (PCs), we generated the conditional knockdown of Ucp4 in PCs (Pcp2cre;Ucp4fl/fl mice) by breeding Ucp4fl/fl mice with Pcp2cre mice. Series results by Western blot, immunofluorescent staining, and triple RNAscope in situ hybridization confirmed the specific ablation of Ucp4 in PCs in Pcp2cre;Ucp4fl/fl mice, but did not affect the expression of Ucp2, the analog of Ucp4. Combined behavioral tests showed that Pcp2cre;Ucp4fl/fl mice displayed a characteristic bradykinesia in the spontaneous movements. The electromyogram recordings detection excluded the possibility of hypotonia in Pcp2cre;Ucp4fl/fl mice. And the electrical patch clamp recordings showed the altered properties of PCs in Pcp2cre;Ucp4fl/fl mice. Moreover, transmission electron microscope (TEM) results showed the increased mitochondrial circularity in PCs; ROS probe imaging showed the increased ROS generation in molecular layer; and finally, microplate reader assay showed the significant changes of mitochondrial functions, including ROS, ATP, and MMP in the isolated cerebellum tissue. The results suggested that the specific knockdown of mitochondrial protein Ucp4 could damage PCs possibly by attacking their mitochondrial function. The present study is the first to report a close relationship between UCP4 deletion with PCs impairment, and suggests the importance of UCP4 in the substantial support of mitochondrial function homeostasis in bradykinesia. UCP4 might be a therapeutic target for the cerebellar-related movement disorder.

Objective assessment of the effects of opicapone in Parkinson's disease through kinematic analysis.

BACKGROUND: Opicapone (OPC) is a third-generation, selective peripheral COMT inhibitor that improves peripheral L-DOPA bioavailability and reduces OFF time and end-of-dose motor fluctuations in Parkinson's disease (PD) patients. OBJECTIVES: In this study, we objectively assessed the effects of adding OPC to L-DOPA on bradykinesia in PD through kinematic analysis of finger movements. METHODS: We enrolled 20 treated patients with PD and motor fluctuations. Patients underwent two experimental sessions (L-DOPA, L-DOPA + OPC), separated by at least 1 week. In each session, patients were clinically evaluated and underwent kinematic movement analysis of repetitive finger movements at four time points: (i) before their usual morning dose of L-DOPA (T0), (ii) 30 min (T1), (iii) 1 h and 30 min (T2), and (iv) 3 h and 30 min after the L-DOPA intake (T3). RESULTS: Movement velocity and amplitude of finger movements were higher in PD patients during the session with OPC compared to the session without OPC at all the time points tested. Importantly, the variability of finger movement velocity and amplitude across T0-T3 was significantly lower in the L-DOPA + OPC than L-DOPA session. CONCLUSIONS: This study is the first objective assessment of the effects of adding OPC to L-DOPA on bradykinesia in patients with PD and motor fluctuations. OPC, in addition to the standard dopaminergic therapy, leads to significant improvements in bradykinesia during clinically relevant periods associated with peripheral L-DOPA dynamics, i.e., the OFF state in the morning, delayed-ON, and wearing-OFF periods.