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The capacity to learn new visuomotor associations is fundamental to adaptive motor behavior. Evidence suggests visuomotor learning deficits in Parkinson's disease (PD). However, the exact nature of these deficits and the ability of dopamine medication to improve them are under-explored. Previous studies suggested that learning driven by large and small movement errors engaged distinct neural mechanisms. Here, we investigated whether PD patients have a generalized impairment in visuomotor learning or selective deficits in learning from large explicit errors which engages cognitive strategies or small imperceptible movement errors involving primarily implicit learning processes. Visuomotor learning skills of non-medicated and medicated patients were assessed in two reaching tasks in which the size of visuospatial errors experienced during learning was manipulated using a novel three-dimensional virtual reality environment. In the explicit perturbation task, the visuomotor perturbation was applied suddenly resulting in large consciously detected initial spatial errors, whereas in the implicit perturbation task, the perturbation was gradually introduced in small undetectable steps such that subjects never experienced large movement errors. A major finding of this study was that PD patients in non-medicated and medicated conditions displayed slower learning rates and smaller adaptation magnitudes than healthy subjects in the explicit perturbation task, but performance similar to healthy controls in the implicit perturbation task. Also, non-medicated patients showed an average reduced deadaptation relative to healthy controls when exposed to the large errors produced by the sudden removal of the perturbation in both the explicit and implicit perturbation tasks. Although dopaminergic medication consistently improved motor signs, it produced a variable impact on learning the explicit perturbation and deadaptation and unexpectedly worsened performance in some patients. Considered together, these results indicate that PD selectively impairs the ability to learn from large consciously detected visuospatial errors. This finding suggests that basal ganglia-related circuits are important neural structures for adaptation to sudden perturbations requiring awareness and high-cost action selection. Dopaminergic treatment may selectively compromise the ability to learn from large explicit movement errors for reasons that remain to be elucidated. [ABSTRACT FROM AUTHOR]

Background and Aims: A reduction in hepatic venous pressure gradient (HVPG) is the most accurate marker for assessing the severity of portal hypertension and the effectiveness of intervention treatments. This study aimed to evaluate the prognostic potential of blood-based proteomic biomarkers in predicting HVPG response amongst cirrhotic patients with portal hypertension due to Hepatitis C virus (HCV) and had achieved sustained virologic response (SVR)., Methods: The study comprised 59 patients from two cohorts. Patients underwent paired HVPG (pretreatment and after SVR), liver stiffness (LSM), and enhanced liver fibrosis scores (ELF) measurements, as well as proteomics-based profiling on serum samples using SomaScan® at baseline (BL) and after SVR (EOS). Machine learning with feature selection (Caret, Random Forest and RPART) methods were performed to determine the proteins capable of classifying HVPG responders. Model performance was evaluated using AUROC (pROC R package)., Results: Patients were stratified by a change in HVPG (EOS vs. BL) into responders (greater than 20% decline in HVPG from BL, or <10 mmHg at EOS with >10 mmHg at BL) and non-responders. LSM and ELF decreased markedly after SVR but did not correlate with HVPG response. SomaScan (SomaLogic, Inc., Boulder, CO) analysis revealed a substantial shift in the peripheral proteome composition, reflected by 82 significantly differentially abundant proteins. Twelve proteins accurately distinguished responders from non-responders, with an AUROC of .86, sensitivity of 83%, specificity of 83%, accuracy of 83%, PPV of 83%, and NPV of 83%., Conclusions: A combined non-invasive soluble protein signature was identified, capable of accurately predicting HVPG response in HCV liver cirrhosis patients after achieving SVR., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-complete spinal cord injury (SCI) has ever been developed. We assessed the safety and efficacy of an activator of spinal locomotor neurons in humans, which were shown in paraplegic animals to elicit temporary episodes of involuntary walking., Methods: Single administration of buspirone/levodopa/carbidopa (SpinalonTM), levodopa/carbidopa (ratio 4: 1), and buspirone or placebo was performed using a dose-escalation design in 45 subjects placed in supine position who had had an SCI classified as complete (AIS A) or motor-complete/sensory incomplete (AIS B) for at least 3 months. Blood samples before and at regular intervals (15, 30, 60, 120, 240 min) after treatment were collected for hematological and pharmacokinetic (PK) analyses. Electromyographic (EMG) activity of eight muscles (four per leg) was monitored prior to and at several time points after drug administration., Results: SpinalonTM (10-35 mg buspirone/100-350 mg levodopa/25-85 mg carbidopa) displayed no sign of safety concerns - only mild nausea was found in 3 cases. At higher doses, 50 mg/500 mg/125 mg SpinalonTM was considered to have reached maximum tolerated dose (MTD) since 3 out of 4 subjects experienced related adverse events including vomiting. PK analyses showed comparable data between groups suggesting no significant drugdrug interaction with SpinalonTM. Only the SpinalonTM-treated groups displayed significant EMG activity accompanied by locomotor-like characteristics - that is with rhythmic and bilaterally alternating bursts., Conclusion: Therefore, this study provides evidence of safety and preliminary efficacy following a single administration of SpinalonTM in subjects with SCI., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Evidence suggests that Parkinson's disease (PD) patients produce large spatial errors when reaching to proprioceptively defined targets. Here, we examined whether these movement inaccuracies result mainly from impaired use of proprioceptive inputs for movement planning mechanisms or from on-line movement guidance. Medicated and non-medicated PD patients and healthy controls performed three-dimensional reaching movements in four sensorimotor conditions that increase proprioceptive processing requirements. We assessed the influence of these sensorimotor conditions on the final accuracy and initial kinematics of the movements. If the patterns of final errors are primarily determined by planning processes before the initiation of the movement, the initial kinematics of reaching movements should show similar trends and predict the pattern of final errors. Medicated and non-medicated PD patients showed a greater mean level of final 3D errors than healthy controls when proprioception was the sole source of information guiding the movement, but this difference reached significance only for medicated PD patients. However, the pattern of initial kinematics and final spatial errors were markedly different both between sensorimotor conditions and between groups. Furthermore, medicated and non-medicated PD patients were less efficient than healthy controls in compensating for their initial spatial errors (hand distance from target location at peak velocity) when aiming at proprioceptively defined compared to visually defined targets. Considered together, the results are consistent with a selective deficit in proprioceptively based movement guidance in PD. Furthermore, dopaminergic medication did not improve proprioceptively guided movements in PD patients, indicating that dopaminergic dysfunction within the basal ganglia is not solely responsible for these deficits.

Context: The known detrimental effects of sport concussions on motor system function include balance problems, slowed motor execution, and abnormal motor cortex excitability., Objective: To assess whether these concussion-related alterations of motor system function are still evident in collegiate football players who sustained concussions but returned to competition more than 9 months before testing., Design: Case-control study., Setting: University laboratory., Patients or Other Participants: A group of 21 active, university-level football players who had experienced concussions was compared with 15 university football players who had not sustained concussions., Intervention(s): A force platform was used to assess center-of-pressure (COP) displacement and COP oscillation regularity (approximate entropy) as measures of postural stability in the upright position. A rapid alternating-movement task was also used to assess motor execution speed. Transcranial magnetic stimulation over the motor cortex was used to measure long-interval intracortical inhibition and the cortical silent period, presumably reflecting y-aminobutyric acid subtype B receptor-mediated intracortical inhibition., Main Outcome Measure(s): COP displacement and oscillation regularity, motor execution speed, long-interval intracortical inhibition, cortical silent period., Results: Relative to controls, previously concussed athletes showed persistently lower COP oscillation randomness, normal performance on a rapid alternating-movement task, and more M1 intracortical inhibition that was related to the number of previous concussions., Conclusions: Sport concussions were associated with pervasive changes in postural control and more M1 intracortical inhibition, providing neurophysiologic and behavioral evidence of lasting, subclinical changes in motor system integrity in concussed athletes.