Mesoscale simulations predict the role of synergistic cerebellar plasticity during classical eyeblink conditioning.

According to the motor learning theory by Albus and Ito, synaptic depression at the parallel fibre to Purkinje cells synapse (pf-PC) is the main substrate responsible for learning sensorimotor contingencies under climbing fibre control. However, recent experimental evidence challenges this relatively monopolistic view of cerebellar learning. Bidirectional plasticity appears crucial for learning, in which different microzones can undergo opposite changes of synaptic strength (e.g. downbound microzones-more likely depression, upbound microzones-more likely potentiation), and multiple forms of plasticity have been identified, distributed over different cerebellar circuit synapses. Here, we have simulated classical eyeblink conditioning (CEBC) using an advanced spiking cerebellar model embedding downbound and upbound modules that are subject to multiple plasticity rules. Simulations indicate that synaptic plasticity regulates the cascade of precise spiking patterns spreading throughout the cerebellar cortex and cerebellar nuclei. CEBC was supported by plasticity at the pf-PC synapses as well as at the synapses of the molecular layer interneurons (MLIs), but only the combined switch-off of both sites of plasticity compromised learning significantly. By differentially engaging climbing fibre information and related forms of synaptic plasticity, both microzones contributed to generate a well-timed conditioned response, but it was the downbound module that played the major role in this process. The outcomes of our simulations closely align with the behavioural and electrophysiological phenotypes of mutant mice suffering from cell-specific mutations that affect processing of their PC and/or MLI synapses. Our data highlight that a synergy of bidirectional plasticity rules distributed across the cerebellum can facilitate finetuning of adaptive associative behaviours at a high spatiotemporal resolution.

Improvement of speed-accuracy tradeoff during practice of a point-to-point task in children with acquired dystonia.

The tradeoff between speed and accuracy is a well-known constraint for human movement, but previous work has shown that this tradeoff can be modified by practice, and the quantitative relationship between speed and accuracy may be an indicator of skill in some tasks. We have previously shown that children with dystonia are able to adapt their movement strategy in a ballistic throwing game to compensate for increased variability of movement. Here, we test whether children with dystonia can adapt and improve skills learned on a trajectory task. We use a novel task in which children move a spoon with a marble between two targets. Difficulty is modified by changing the depth of the spoon. Our results show that both healthy children and children with acquired dystonia move more slowly with the more difficult spoons, and both groups improve the relationship between speed and spoon difficulty following 1 wk of practice. By tracking the marble position in the spoon, we show that children with dystonia use a larger fraction of the available variability, whereas healthy children adopt a much safer strategy and remain farther from the margins, as well as learning to adapt and have more control over the marble's utilized area by practice. Together, our results show that both healthy children and children with dystonia choose trajectories that compensate for risk and inherent variability, and that the increased variability in dystonia can be modified with continued practice.NEW & NOTEWORTHY This study provides insights into the adaptability of children with dystonia in learning a point-to-point task. We show that these children adjust their strategies to account for increased difficulty in the task. Our findings underscore the potential of task-specific practice in improving motor skills and show higher level of signal-dependent noise can be controlled through repetition and learned strategies, which provides an avenue for the quantitative evaluation of rehabilitation strategies in this challenging group.

Technology Acceptance Model for Exoskeletons for Rehabilitation of the Upper Limbs from Therapists' Perspectives.

Over the last few years, exoskeletons have been demonstrated to be useful tools for supporting the execution of neuromotor rehabilitation sessions. However, they are still not very present in hospitals. Therapists tend to be wary of this type of technology, thus reducing its acceptability and, therefore, its everyday use in clinical practice. The work presented in this paper investigates a novel point of view that is different from that of patients, which is normally what is considered for similar analyses. Through the realization of a technology acceptance model, we investigate the factors that influence the acceptability level of exoskeletons for rehabilitation of the upper limbs from therapists' perspectives. We analyzed the data collected from a pool of 55 physiotherapists and physiatrists through the distribution of a questionnaire. Pearson's correlation and multiple linear regression were used for the analysis. The relations between the variables of interest were also investigated depending on participants' age and experience with technology. The model built from these data demonstrated that the perceived usefulness of a robotic system, in terms of time and effort savings, was the first factor influencing therapists' willingness to use it. Physiotherapists' perception of the importance of interacting with an exoskeleton when carrying out an enhanced therapy session increased if survey participants already had experience with this type of rehabilitation technology, while their distrust and the consideration of others' opinions decreased. The conclusions drawn from our analyses show that we need to invest in making this technology better known to the public-in terms of education and training-if we aim to make exoskeletons genuinely accepted and usable by therapists. In addition, integrating exoskeletons with multi-sensor feedback systems would help provide comprehensive information about the patients' condition and progress. This can help overcome the gap that a robot creates between a therapist and the patient's human body, reducing the fear that specialists have of this technology, and this can demonstrate exoskeletons' utility, thus increasing their perceived level of usefulness.

Bayesian Integration in a Spiking Neural System for Sensorimotor Control.

The brain continuously estimates the state of body and environment, with specific regions that are thought to act as Bayesian estimator, optimally integrating noisy and delayed sensory feedback with sensory predictions generated by the cerebellum. In control theory, Bayesian estimators are usually implemented using high-level representations. In this work, we designed a new spike-based computational model of a Bayesian estimator. The state estimator receives spiking activity from two neural populations encoding the sensory feedback and the cerebellar prediction, and it continuously computes the spike variability within each population as a reliability index of the signal these populations encode. The state estimator output encodes the current state estimate. We simulated a reaching task at different stages of cerebellar learning. The activity of the sensory feedback neurons encoded a noisy version of the trajectory after actual movement, with an almost constant intrapopulation spiking variability. Conversely, the activity of the cerebellar output neurons depended on the phase of the learning process. Before learning, they fired at their baseline not encoding any relevant information, and the variability was set to be higher than that of the sensory feedback (more reliable, albeit delayed). When learning was complete, their activity encoded the trajectory before the actual execution, providing an accurate sensory prediction; in this case, the variability was set to be lower than that of the sensory feedback. The state estimator model optimally integrated the neural activities of the afferent populations, so that the output state estimate was primarily driven by sensory feedback in prelearning and by the cerebellar prediction in postlearning. It was able to deal even with more complex scenarios, for example, by shifting the dominant source during the movement execution if information availability suddenly changed. The proposed tool will be a critical block within integrated spiking, brain-inspired control systems for simulations of sensorimotor tasks.

Upper limb soft robotic wearable devices: a systematic review.

INTRODUCTION: Soft robotic wearable devices, referred to as exosuits, can be a valid alternative to rigid exoskeletons when it comes to daily upper limb support. Indeed, their inherent flexibility improves comfort, usability, and portability while not constraining the user's natural degrees of freedom. This review is meant to guide the reader in understanding the current approaches across all design and production steps that might be exploited when developing an upper limb robotic exosuit. METHODS: The literature research regarding such devices was conducted in PubMed, Scopus, and Web of Science. The investigated features are the intended scenario, type of actuation, supported degrees of freedom, low-level control, high-level control with a focus on intention detection, technology readiness level, and type of experiments conducted to evaluate the device. RESULTS: A total of 105 articles were collected, describing 69 different devices. Devices were grouped according to their actuation type. More than 80% of devices are meant either for rehabilitation, assistance, or both. The most exploited actuation types are pneumatic (52%) and DC motors with cable transmission (29%). Most devices actuate 1 (56%) or 2 (28%) degrees of freedom, and the most targeted joints are the elbow and the shoulder. Intention detection strategies are implemented in 33% of the suits and include the use of switches and buttons, IMUs, stretch and bending sensors, EMG and EEG measurements. Most devices (75%) score a technology readiness level of 4 or 5. CONCLUSION: Although few devices can be considered ready to reach the market, exosuits show very high potential for the assistance of daily activities. Clinical trials exploiting shared evaluation metrics are needed to assess the effectiveness of upper limb exosuits on target users.

A unified scheme for the benchmarking of upper limb functions in neurological disorders.

BACKGROUND: In neurorehabilitation, we are witnessing a growing awareness of the importance of standardized quantitative assessment of limb functions. Detailed assessments of the sensorimotor deficits following neurological disorders are crucial. So far, this assessment has relied mainly on clinical scales, which showed several drawbacks. Different technologies could provide more objective and repeatable measurements. However, the current literature lacks practical guidelines for this purpose. Nowadays, the integration of available metrics, protocols, and algorithms into one harmonized benchmarking ecosystem for clinical and research practice is necessary. METHODS: This work presents a benchmarking framework for upper limb capacity. The scheme resulted from a multidisciplinary and iterative discussion among several partners with previous experience in benchmarking methodology, robotics, and clinical neurorehabilitation. We merged previous knowledge in benchmarking methodologies for human locomotion and direct clinical and engineering experience in upper limb rehabilitation. The scheme was designed to enable an instrumented evaluation of arm capacity and to assess the effectiveness of rehabilitative interventions with high reproducibility and resolution. It includes four elements: (1) a taxonomy for motor skills and abilities, (2) a list of performance indicators, (3) a list of required sensor modalities, and (4) a set of reproducible experimental protocols. RESULTS: We proposed six motor primitives as building blocks of most upper-limb daily-life activities and combined them into a set of functional motor skills. We identified the main aspects to be considered during clinical evaluation, and grouped them into ten motor abilities categories. For each ability, we proposed a set of performance indicators to quantify the proposed ability on a quantitative and high-resolution scale. Finally, we defined the procedures to be followed to perform the benchmarking assessment in a reproducible and reliable way, including the definition of the kinematic models and the target muscles. CONCLUSIONS: This work represents the first unified scheme for the benchmarking of upper limb capacity. To reach a consensus, this scheme should be validated with real experiments across clinical conditions and motor skills. This validation phase is expected to create a shared database of human performance, necessary to have realistic comparisons of treatments and drive the development of new personalized technologies.

User-centred assistive SystEm for arm Functions in neUromuscuLar subjects (USEFUL): a randomized controlled study.

BACKGROUND: Upper limb assistive devices can compensate for muscular weakness and empower the user in the execution of daily activities. Multiple devices have been recently proposed but there is still a lack in the scientific comparison of their efficacy. METHODS: We conducted a cross-over multi-centric randomized controlled trial to assess the functional improvement at the upper limb level of two arms supports on 36 patients with muscular dystrophy. Participants tested a passive device (i.e., Wrex by Jaeco) and a semi-active solution for gravity compensation (i.e., Armon Ayura). We evaluated devices' effectiveness with an externally-assessed scale (i.e., Performance of the Upper Limb-PUL-module), a self-perceived scale (i.e., Abilhand questionnaire), and a usability scale (i.e., System Usability Scale). Friedman's test was used to assess significant functional gain for PUL module and Abilhand questionnaire. Moreover, PUL changes were compared by means of the Friedman's test. RESULTS: Most of the patients improved upper limb function with the use of arm supports (median PUL scores increase of 1-3 points). However, the effectiveness of each device was related to the level of residual ability of the end-user. Slightly impaired patients maintained the same independence without and with assistive devices, even if they reported reduced muscular fatigue for both devices. Moderately impaired patients enhanced their arm functionality with both devices, and they obtained higher improvements with the semi-active one (median PUL scores increase of 9 points). Finally, severely impaired subjects benefited only from the semi-active device (median PUL scores increase of 12 points). Inadequate strength was recognized as a barrier to passive devices. The usability, measured by the System Usability Scale, was evaluated by end-users "good" (70/100 points) for the passive, and "excellent" (80/100 points) for the semi-active device. CONCLUSIONS: This study demonstrated that assistive devices can improve the quality of life of people suffering from muscular dystrophy. The use of passive devices, despite being low cost and easy to use, shows limitations in the efficacy of the assistance to daily tasks, limiting the assistance to a predefined horizontal plane. The addition of one active degree of freedom improves efficacy and usability especially for medium to severe patients. Further investigations are needed to increase the evidence on the effect of arm supports on quality of life and diseases' progression in subjects with degenerative disorders. Trial registration clinicaltrials.gov, NCT03127241, Registered 25th April 2017. The clinical trial was also registered as a post-market study at the Italian Ministry of Health.

Towards a Functional Performance Validation Standard for Industrial Low-Back Exoskeletons: State of the Art Review.

While the research interest for exoskeletons has been rising in the last decades, missing standards for their rigorous evaluation are potentially limiting their adoption in the industrial field. In this context, exoskeletons for worker support have the aim to reduce the physical effort required by humans, with dramatic social and economic impact. Indeed, exoskeletons can reduce the occurrence and the entity of work-related musculoskeletal disorders that often cause absence from work, resulting in an eventual productivity loss. This very urgent and multifaceted issue is starting to be acknowledged by researchers. This article provides a systematic review of the state of the art for functional performance evaluation of low-back exoskeletons for industrial workers. We report the state-of-the-art evaluation criteria and metrics used for such a purpose, highlighting the lack of a standard for this practice. Very few studies carried out a rigorous evaluation of the assistance provided by the device. To address also this topic, the article ends with a proposed framework for the functional validation of low-back exoskeletons for the industry, with the aim to pave the way for the definition of rigorous industrial standards.

Does cycling induced by functional electrical stimulation enhance motor recovery in the subacute phase after stroke? A systematic review and meta-analysis.

OBJECTIVE: To investigate the effects of cycling with functional electrical stimulation on walking, muscle power and tone, balance and activities of daily living in subacute stroke survivors. DATA SOURCES: Ten electronic databases were searched from inception to February 2020. REVIEW METHODS: Inclusion criteria were: subacute stroke survivors (<6 months since stroke), an experimental group performing any type of cycling training with electrical stimulation, alone or in addition to usual care, and a control group performing usual care alone. Two reviewers assessed eligibility, extracted data and analyzed the risks of bias. Standardized Mean Difference (SMD) or Mean Difference (MD) with 95% Confidence Intervals (CI) were estimated using fixed- or random-effects models to evaluate the training effect. RESULTS: Seven randomized controlled trials recruiting a total of 273 stroke survivors were included in the meta-analyses. There was a statistically significant, but not clinically relevant, effect of cycling with electrical stimulation compared to usual care on walking (six studies, SMD [95% CI] = 0.40 [0.13, 0.67]; P = 0.004), capability to maintain a sitting position (three studies, MD [95% CI] = 7.92 [1.01, 14.82]; P = 0.02) and work produced by the paretic leg during pedaling (2 studies, MD [95% CI] = 8.13 [1.03, 15.25]; P = 0.02). No significant between-group differences were found for muscular power, tone, standing balance, and activities of daily living. CONCLUSIONS: Cycling training with functional electrical stimulation cannot be recommended in terms of being better than usual care in subacute stroke survivors. Further investigations are required to confirm these results, to determine the optimal training parameters and to evaluate long-term effects.

Characterization of Synovial Cytokine Patterns in Bucket-Handle and Posterior Horn Meniscal Tears.

The specific etiology of meniscal tears, including the mechanism of lesion, location, and orientation, is considered for its contribution to subsequent joint cytokine responsiveness, healing outcomes, and by extension, appropriate lesion-specific surgical remediation. Meniscal repair is desirable to reduce the probability of development of posttraumatic osteoarthritis (PTOA) which is strongly influenced by the coordinate generation of pro- and anti-inflammatory cytokines by the injured cartilage. We now present biochemical data on variation in cytokine levels arising from two particular meniscal tears: bucket-handle (BH) and posterior horn (PH) isolated meniscal tears. We selected these two groups due to the different clinical presentations. We measured the concentrations of TNF-α, IL-1ß, IL-6, IL-8, and IL-10 in knee synovial fluid of 45 patients with isolated meniscal lesions (BH tear, n = 12; PH tear, n = 33). TNF-α levels were significantly (p < 0.05) greater in the BH group compared with the PH group, whereas IL-1ß levels were significantly greater (p < 0.05) in the PH group compared with the BH group. Both BH and PH groups were consistent in presenting a positive correlation between concentrations of IL-6 and IL-1ß. A fundamental difference in IL-10 responsiveness between the two groups was noted; specifically, levels of IL-10 were positively correlated with IL-6 in the BH group, whereas in the PH group, levels of IL-10 were positively correlated with IL-1ß. Collectively, our data suggest a possible influence of the meniscal tear pattern to the articular cytokine responsiveness. This differential expression of inflammatory cytokines may influence the risk of developing PTOA in the long term.

Changes in leg cycling muscle synergies after training augmented by functional electrical stimulation in subacute stroke survivors: a pilot study.

BACKGROUND: Muscle synergies analysis can provide a deep understanding of motor impairment after stroke and of changes after rehabilitation. In this study, the neuro-mechanical analysis of leg cycling was used to longitudinally investigate the motor recovery process coupled with cycling training augmented by Functional Electrical Stimulation (FES) in subacute stroke survivors. METHODS: Subjects with ischemic subacute stroke participated in a 3-week training of FES-cycling with visual biofeedback plus usual care. Participants were evaluated before and after the intervention through clinical scales, gait spatio-temporal parameters derived from an instrumented mat, and a voluntary pedaling test. Biomechanical metrics (work produced by the two legs, mechanical effectiveness and symmetry indexes) and bilateral electromyography from 9 leg muscles were acquired during the voluntary pedaling test. To extract muscles synergies, the Weighted Nonnegative Matrix Factorization algorithm was applied to the normalized EMG envelopes. Synergy complexity was measured by the number of synergies required to explain more than 90% of the total variance of the normalized EMG envelopes and variance accounted for by one synergy. Regardless the inter-subject differences in the number of extracted synergies, 4 synergies were extracted from each patient and the cosine-similarity between patients and healthy weight vectors was computed. RESULTS: Nine patients (median age of 75 years and median time post-stroke of 2 weeks) were recruited. Significant improvements in terms of clinical scales, gait parameters and work produced by the affected leg were obtained after training. Synergy complexity well correlated to the level of motor impairment at baseline, but it did not change after training. We found a significant improvement in the similarity of the synergy responsible of the knee flexion during the pulling phase of the pedaling cycle, which was the mostly compromised at baseline. This improvement may indicate the re-learning of a more physiological motor strategy. CONCLUSIONS: Our findings support the use of the neuro-mechanical analysis of cycling as a method to assess motor recovery after stroke, mainly in an early phase, when gait evaluation is not yet possible. The improvement in the modular coordination of pedaling correlated with the improvement in motor functions and walking ability achieved at the end of the intervention support the role of FES-cycling in enhancing motor re-learning after stroke but need to be confirmed in a controlled study with a larger sample size. TRIAL REGISTRATION: ClinicalTrial.gov, NCT02439515. Registered on May 8, 2015, .

EMG-based vibro-tactile biofeedback training: effective learning accelerator for children and adolescents with dystonia? A pilot crossover trial.

BACKGROUND: This study is aimed at better understanding the role of a wearable and silent ElectroMyoGraphy-based biofeedback on motor learning in children and adolescents with primary and secondary dystonia. METHODS: A crossover study with a wash-out period of at least 1 week was designed; the device provides the patient with a vibration proportional to the activation of an impaired target muscle. The protocol consisted of two 5-day blocks during which subjects were trained and tested on a figure-8 writing task: their performances (at different levels of difficulty) were evaluated in terms of both kinematics and muscular activations on day 1 and day 5, while the other 3 days were purely used as training sessions. The training was performed with and without using the biofeedback device: the week of use was randomized. Data were collected on 14 subjects with primary and secondary (acquired) dystonia (age: 6-19 years). RESULTS: Results comparing kinematic-based and EMG-based outcome measures pre- and post-training showed learning due to practice for both subjects with primary and secondary dystonia. On top of said learning, an improvement in terms of inter-joint coordination and muscular pattern functionality was recorded only for secondary dystonia subjects, when trained with the aid of the EMG-based biofeedback device. CONCLUSIONS: Our results support the hypothesis that children and adolescents with primary dystonia in which there is intact sensory processing do not benefit from feedback augmentation, whereas children with secondary dystonia, in which sensory deficits are often present, exhibit a higher learning capacity when augmented movement-related sensory information is provided. This study represents a fundamental investigation to address the scarcity of noninvasive therapeutic interventions for young subjects with dystonia.

Intra-Articular Cytokine Levels in Adolescent Patients after Anterior Cruciate Ligament Tear.

The treatment of anterior cruciate ligament (ACL) injuries in children and adolescents is challenging. Preclinical and clinical studies investigated ACL repairing techniques in skeletally immature subjects. However, intra-articular bioenvironment following ACL tear has not yet been defined in skeletally immature patients. The aim of this study was to measure cytokine concentrations in the synovial fluid in adolescent population. Synovial levels of IL-1ß, IL-1ra, IL-6, IL-8, IL-10, and TNF-α were measured in 17 adolescent patients (15 boys) with ACL tears who underwent ACL reconstruction including acute (5), subacute (7), and chronic (5) phases. Femoral growth plates were classified as "open" in three patients, "closing" in eight, and "closed" in six. Eleven patients presented an ACL tear associated with a meniscal tear. The mean Tegner and Lysholm scores (mean ± SD) of all patients were 8 ± 1 and 50.76 ± 26, respectively. IL-8, TNF-α, and IL-1ß levels were significantly greater in patients with "open" physes. IL-1ra and IL-1ß levels were significantly higher in patients with ACL tear associated with a meniscal tear. Poor Lysholm scores were associated with elevated IL-6 and IL-10 levels. IL-10 levels positively correlated with IL-6 and IL-8 levels, whereas TNF-α concentration negatively correlated with IL-6 levels. Skeletally immature patients with meniscal tears and open growth plates have a characteristic cytokine profile with particularly elevated levels of proinflammatory cytokines including IL-8, TNF-α, and IL-1ß. This picture suggests that the ACL tear could promote an intra-articular catabolic response in adolescent patients greater than that generally reported for adult subjects. The study lacks the comparison with synovial samples from healthy skeletally immature knees due to ethical reasons. Overall, these data contribute to a better knowledge of adolescent intra-articular bioenvironment following ACL injuries.

Group-based multimodal exercises integrated with cognitive-behavioural therapy improve disability, pain and quality of life of subjects with chronic neck pain: a randomized controlled trial with one-year follow-up.

OBJECTIVE: To evaluate the effect of a group-based multidisciplinary rehabilitation programme on disability, pain and quality of life in subjects with chronic neck pain. DESIGN: Randomized controlled trial. SETTING: Specialized rehabilitation centre. SUBJECTS: A total of 170 patients (mean age of 53 years (13); 121 females). INTERVENTIONS: The multidisciplinary group underwent a multidisciplinary rehabilitation programme combining multimodal exercises with psychologist-lead cognitive-behavioural therapy sessions. The general exercise group underwent general physiotherapy. Both groups followed group-based programmes once a week for ten weeks. Additionally, the multidisciplinary group met with the psychologist once a week for a 60-minute session. MAIN MEASURES: The Neck Disability Index (primary outcome), the Tampa Scale for Kinesiophobia, the Pain Catastrophizing Scale, a pain numerical rating scale and the Short-Form Health Survey. The participants were evaluated before, after training and after 12 months. RESULTS: A linear mixed model for repeated measures was used for each outcome measure. Significant effects ( p-value <0.001) were found over time and between groups for all outcome measures. After training, significant improvements were found for both groups for all outcome measures except kinesiophobia and catastrophizing, which did not change in the control group; however, the improvements were significantly greater for the multidisciplinary group. At 12-month follow-up a clinically meaningful between-group difference of 12.4 Neck Disability Index points was found for disability. CONCLUSIONS: A group-based multidisciplinary rehabilitation programme including cognitive-behavioural therapy was superior to group-based general physiotherapy in improving disability, pain and quality of life of subjects with chronic neck pain. The effects lasted for at least one year.

Distributed Circuit Plasticity: New Clues for the Cerebellar Mechanisms of Learning.

The cerebellum is involved in learning and memory of sensory motor skills. However, the way this process takes place in local microcircuits is still unclear. The initial proposal, casted into the Motor Learning Theory, suggested that learning had to occur at the parallel fiber-Purkinje cell synapse under supervision of climbing fibers. However, the uniqueness of this mechanism has been questioned, and multiple forms of long-term plasticity have been revealed at various locations in the cerebellar circuit, including synapses and neurons in the granular layer, molecular layer and deep-cerebellar nuclei. At present, more than 15 forms of plasticity have been reported. There has been a long debate on which plasticity is more relevant to specific aspects of learning, but this question turned out to be hard to answer using physiological analysis alone. Recent experiments and models making use of closed-loop robotic simulations are revealing a radically new view: one single form of plasticity is insufficient, while altogether, the different forms of plasticity can explain the multiplicity of properties characterizing cerebellar learning. These include multi-rate acquisition and extinction, reversibility, self-scalability, and generalization. Moreover, when the circuit embeds multiple forms of plasticity, it can easily cope with multiple behaviors endowing therefore the cerebellum with the properties needed to operate as an effective generalized forward controller.

Development of a bench-top device for parallel climate-controlled recordings of neuronal cultures activity with microelectrode arrays.

Two binding requirements for in vitro studies on long-term neuronal networks dynamics are (i) finely controlled environmental conditions to keep neuronal cultures viable and provide reliable data for more than a few hours and (ii) parallel operation on multiple neuronal cultures to shorten experimental time scales and enhance data reproducibility. In order to fulfill these needs with a Microelectrode Arrays (MEA)-based system, we designed a stand-alone device that permits to uninterruptedly monitor neuronal cultures activity over long periods, overcoming drawbacks of existing MEA platforms. We integrated in a single device: (i) a closed chamber housing four MEAs equipped with access for chemical manipulations, (ii) environmental control systems and embedded sensors to reproduce and remotely monitor the standard in vitro culture environment on the lab bench (i.e. in terms of temperature, air CO2 and relative humidity), and (iii) a modular MEA interface analog front-end for reliable and parallel recordings. The system has been proven to assure environmental conditions stable, physiological and homogeneos across different cultures. Prolonged recordings (up to 10 days) of spontaneous and pharmacologically stimulated neuronal culture activity have not shown signs of rundown thanks to the environmental stability and have not required to withdraw the cells from the chamber for culture medium manipulations. This system represents an effective MEA-based solution to elucidate neuronal network phenomena with slow dynamics, such as long-term plasticity, effects of chronic pharmacological stimulations or late-onset pathological mechanisms.

Effects of ACL Reconstructive Surgery on Temporal Variations of Cytokine Levels in Synovial Fluid.

Anterior cruciate ligament (ACL) reconstruction restores knee stability but does not reduce the incidence of posttraumatic osteoarthritis induced by inflammatory cytokines. The aim of this research was to longitudinally measure IL-1ß, IL-6, IL-8, IL-10, and TNF-α levels in patients subjected to ACL reconstruction using bone-patellar tendon-bone graft. Synovial fluid was collected within 24-72 hours of ACL rupture (acute), 1 month after injury immediately prior to surgery (presurgery), and 1 month thereafter (postsurgery). For comparison, a "control" group consisted of individuals presenting chronic ACL tears. Our results indicate that levels of IL-6, IL-8, and IL-10 vary significantly over time in reconstruction patients. In the acute phase, the levels of these cytokines in reconstruction patients were significantly greater than those in controls. In the presurgery phase, cytokine levels in reconstruction patients were reduced and comparable with those in controls. Finally, cytokine levels increased again with respect to control group in the postsurgery phase. The levels of IL-1ß and TNF-α showed no temporal variation. Our data show that the history of an ACL injury, including trauma and reconstruction, has a significant impact on levels of IL-6, IL-8, and IL-10 in synovial fluid but does not affect levels of TNF-α and IL-1ß.

The Neural Correlates of Long-Term Carryover following Functional Electrical Stimulation for Stroke.

Neurorehabilitation effective delivery for stroke is likely to be improved by establishing a mechanistic understanding of how to enhance adaptive plasticity. Functional electrical stimulation is effective at reducing poststroke foot drop; in some patients, the effect persists after therapy has finished with an unknown mechanism. We used fMRI to examine neural correlates of functional electrical stimulation key elements, volitional intent to move and concurrent stimulation, in a group of chronic stroke patients receiving functional electrical stimulation for foot-drop correction. Patients exhibited task-related activation in a complex network, sharing bilateral sensorimotor and supplementary motor activation with age-matched controls. We observed consistent separation of patients with and without carryover effect on the basis of brain responses. Patients who experienced the carryover effect had responses in supplementary motor area that correspond to healthy controls; the interaction between experimental factors in contralateral angular gyrus was seen only in those without carryover. We suggest that the functional electrical stimulation carryover mechanism of action is based on movement prediction and sense of agency/body ownership-the ability of a patient to plan the movement and to perceive the stimulation as a part of his/her own control loop is important for carryover effect to take place.

Increased task-uncorrelated muscle activity in childhood dystonia.

BACKGROUND: Even if movement abnormalities in dystonia are obvious on observation-based examinations, objective measures to characterize dystonia and to gain insights into its pathophysiology are still strongly needed. We hypothesize that motor abnormalities in childhood dystonia are partially due to the inability to suppress involuntary variable muscle activity irrelevant to the achievement of the desired motor task, resulting in the superposition of unwanted motion components on the desired movement. However, it is difficult to separate and quantify appropriate and inappropriate motor signals combined in the same muscle, especially during movement. METHODS: We devise an innovative and practical method to objectively measure movement abnormalities during the performance of a continuous figure-eight writing task in 7 children with dystonia and 9 age-matched healthy controls. During the execution of a continuous writing task, muscle contractions should occur at frequencies that match the frequencies of the writing outcome. We compare the power spectra of kinematic trajectories and electromyographic signals of 8 upper limb muscles to separate muscle activity with the same frequency content of the figure-eight movement (task-correlated) from activity occurring at frequencies extraneous to the task (task-uncorrelated). RESULTS: Children with dystonia present a greater magnitude of task-uncorrelated muscle components. The motor performance achieved by children with dystonia is characterized by an overall lower quality, with high spatial and temporal variability and an altered trade-off between speed and accuracy. CONCLUSIONS: Findings are consistent with the hypothesis that, in childhood dystonia, the ability to appropriately suppress variable and uncorrelated elements of movement is impaired. Here we present a proof-of-concept of a promising tool to characterize the phenomenology of movement disorders and to inform the design of neurorehabilitation therapies.

Re-thinking the role of motor cortex: context-sensitive motor outputs?

The standard account of motor control considers descending outputs from primary motor cortex (M1) as motor commands and efference copy. This account has been challenged recently by an alternative formulation in terms of active inference: M1 is considered as part of a sensorimotor hierarchy providing top-down proprioceptive predictions. The key difference between these accounts is that predictions are sensitive to the current proprioceptive context, whereas efference copy is not. Using functional electric stimulation to experimentally manipulate proprioception during voluntary movement in healthy human subjects, we assessed the evidence for context sensitive output from M1. Dynamic causal modeling of functional magnetic resonance imaging responses showed that FES altered proprioception increased the influence of M1 on primary somatosensory cortex (S1). These results disambiguate competing accounts of motor control, provide some insight into the synaptic mechanisms of sensory attenuation and may speak to potential mechanisms of action of FES in promoting motor learning in neurorehabilitation.