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International audience; BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10(-8)) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

International audience; Pax4 belongs to the paired-box family of transcription factors. The analysis of loss- and gain-of-function mutant animals revealed that this factor plays a crucial role in the endocrine pancreas. Indeed, Pax4 is required for the genesis of insulin-producing beta-cells. Remarkably, the sole misexpression of Pax4 in glucagon-expressing cells is able to induce their regeneration, endow these with beta-cell features, and thereby counter chemically induced diabetes. However, the function of Pax4 in adult endocrine cells remains unclear. Herein, we report the generation of Pax4 conditional knockout mice that will allow the analysis of Pax4 function in mature beta-cells, as well as in the adult central nervous system.

International audience; Drosophila melanogaster is a model organism rich in genetic tools to manipulate and identify neural circuits involved in specific behaviors. Here we present a technique for two-photon calcium imaging in the central brain of head-fixed Drosophila walking on an air-supported ball. The ball's motion is tracked at high resolution and can be treated as a proxy for the fly's own movements. We used the genetically encoded calcium sensor, GCaMP3.0, to record from important elements of the motion-processing pathway, the horizontal-system lobula plate tangential cells (LPTCs) in the fly optic lobe. We presented motion stimuli to the tethered fly and found that calcium transients in horizontal-system neurons correlated with robust optomotor behavior during walking. Our technique allows both behavior and physiology in identified neurons to be monitored in a genetic model organism with an extensive repertoire of walking behaviors.

PURPOSE: Recent evidence indicates that anodal transcranial direct current stimulation (tDCS) can selectively alter the EMG/force relationship of agonist arm muscles; however, the mechanisms mediating those changes are less clear. The purpose of this study was to evaluate the effect of anodal tDCS on motor unit synchronization by using a sophisticated non-linear EMG analysis called recurrence quantification analysis (RQA). METHODS: Surface EMG signals were collected from the biceps brachii muscle of eighteen healthy young adults (9 tDCS and 9 control) at various force levels (12.5%, 25%, 37.5%, and 50% maximum) before and after the application of anodal tDCS over the primary motor cortex. RQA was employed to quantify the changes in percentage of determinism (%DET) and laminarity (%LAM) of the surface EMG signals, which are surrogate measures of motor unit synchronization. RESULTS: RQA analyses indicated that the changes in %DET and %LAM scores were significantly higher in the tDCS group than in the control group (p < 0.05) and this effect was particularly pronounced at higher force levels. CONCLUSION: The results of this study provide novel evidence supporting that anodal tDCS significantly alters motor unit firing strategies (i.e., the degree of synchronization) of the biceps brachii muscle. KEYWORDS: Recurrence analysis; brain stimulation; electromyography; motor unit; nonlinear analysis; synchronization

International audience; The aim of this study was to compare the time course of motion-related source activities evoked by the onset of different kinds of visual motion stimuli in human subjects. Event-related potentials (ERP) were recorded from 64 scalp electrodes in ten healthy subjects while they were viewing four different types of motion stimuli (translation, rotation, expansion and contraction). Following a new approach combining a current density reconstruction with clustering algorithms, source maxima in the time range from 50 to 400 ms after the onset of the visual stimulus were localized and the time courses of activation were elaborated. Six regions contributed significantly to source activity, half originating in the occipital lobe and half in the right parietal and right temporal cortex. The comparison of their time courses led to the following conclusions: (i) the different kinds of motion stimuli activated about the same areas of the brain but with different temporal patterns. (ii) Mainly parietal and extrastriate areas, but not V1/V2, were significantly involved in the differentiation of different kinds of motion. (iii) Contrasting the different kinds of motion onsets, responses from parietal areas were found mainly before those from lateral occipital areas. (iv) The classically defined N2 and P2 components were significantly different among the four motion conditions, but not P1. The N2 motion-related component was elicited not only by lateral occipital areas and middle temporal areas but also by right parietal areas. (v) The rotation condition evoked a novel component P180, concomitant with an increased activity in the left middle temporal gyrus.

A method for electroencephalography (EEG) - near-infrared spectroscopy (NIRS) based assessment of neurovascular coupling (NVC) during anodal transcranial direct current stimulation (tDCS). Anodal tDCS modulates cortical neural activity leading to a hemodynamic response, which was used to identify impaired NVC functionality. In this study, the hemodynamic response was estimated with NIRS. NIRS recorded changes in oxy-hemoglobin (HbO2) and deoxy-hemoglobin (Hb) concentrations during anodal tDCS-induced activation of the cortical region located under the electrode and in-between the light sources and detectors. Anodal tDCS-induced alterations in the underlying neuronal current generators were also captured with EEG. Then, a method for the assessment of NVC underlying the site of anodal tDCS was proposed that leverages the Hilbert-Huang Transform. The case series including four chronic (>6�months) ischemic stroke survivors (3 males, 1 female from age 31 to 76) showed non-stationary effects of anodal tDCS on EEG that correlated with the HbO2 response. Here, the initial dip in HbO2 at the beginning of anodal tDCS corresponded with an increase in the log-transformed mean-power of EEG within 0.5Hz-11.25Hz frequency band. The cross-correlation coefficient changed signs but was comparable across subjects during and after anodal tDCS. The log-transformed mean-power of EEG lagged HbO2 response during tDCS but then led post-tDCS. This case series demonstrated changes in the degree of neurovascular coupling to a 0.526�A/m2 square-pulse (0�30�s) of anodal tDCS. The initial dip in HbO2 needs to be carefully investigated in a larger cohort, for example in patients with small vessel disease. � 2015, Springer Science+Business Media New York.

Stroke is caused when an artery carrying blood from heart to an area in the brain bursts or a clot obstructs the blood flow thereby preventing delivery of oxygen and nutrients. About half of the stroke survivors are left with some degree of disability. Innovative methodologies for restorative neurorehabilitation are urgently required to reduce long-term disability. The ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections is called neuroplasticity. Neuroplasticity is involved in post-stroke functional disturbances, but also in rehabilitation. It has been shown that active cortical participation in a closed-loop brain machine interface (BMI) can induce neuroplasticity in cortical networks where the brain acts as a controller, e.g., during a visuomotor task. Here, the motor task can be assisted with neuromuscular electrical stimulation (NMES) where the BMI will act as a real-time decoder. However, the cortical control and induction of neuroplasticity in a closed-loop brain machine interface is also dependent on the state of brain, e.g., visuospatial attention during visuomotor task performance. In fact, spatial neglect is a hidden disability that is a common complication of stroke and is associated with prolonged hospital stays, accidents, falls, safety problems and chronic functional disability. This hypothesis and theory article presents a multi-level electrotherapy paradigm towards motor rehabilitation in virtual reality that postulates that while the brain acts as a controller in a closed-loop BMI to drive NMES, the state of brain can be can be altered towards improvement of visuomotor task performance with non-invasive brain stimulation. This leads to a multi-level electrotherapy paradigm where a virtual reality-based adaptive response technology is proposed for post-stroke balance rehabilitation. In this article, we present a conceptual review of the related experimental findings., by Uttama Lahiri et. al.

International audience; The World Health Organization estimated that major depression is the fourth most significant cause of disability worldwide for people aged 65 and older, where depressed older adults reported decreased independence, poor health, poor quality of life, functional decline, disability, and increased chronic medical problems. Therefore, the objectives of this study were (1) to develop a low-cost point-of-care testing system for psychomotor symptoms of depression and (2) to evaluate the system in community dwelling elderly in India. The preliminary results from the cross-sectional study showed a significant negative linear correlation between balance and depression. Here, monitoring quantitative electroencephalography along with the center of pressure for cued response time during functional reach tasks may provide insights into the psychomotor symptoms of depression where average slope of the Theta-Alpha power ratio versus average slope of baseline-normalized response time may be a candidate biomarker, which remains to be evaluated in our future clinical studies. Once validated, the biomarker can be used for monitoring the outcome of a comprehensive therapy program in conjunction with pharmacological interventions. Furthermore, the frequency of falls can be monitored with a mobile phone-based application where the propensity of falls during the periods of psychomotor symptoms of depression can be investigated further.

International audience; Functional Electrical Stimulation (FES) facilitates ambulatory function after paralysis by electrically activating the muscles of the lower extremities. The Odstock Dropped Foot Stimulator (ODFS, Odstock, UK) called ODFS Pace, was used for heel-switch triggered FES-assisted walking. The ODFS is recommended as an intervention for neurologically impaired gait in the Royal College of Physicians (UK) Clinical Guidelines on Stroke. Based on the guidelines by the National Institute of Clinical Excellence (NICE, UK), we started first clinical study in India on ODFS Pace as an orthotic intervention for daily use. In this preliminary study, we also investigated improvement in volitional walking following 6 sessions (3 times per week, for 2 weeks) of 30 minutes of FES-assisted treadmill walking on 7 chronic (>6 months after stroke) stroke survivors. We found that short-duration, moderately intensive FES-assisted gait therapy improved volitional gait in 3 out of 7 stroke survivors suffering from foot drop. Even in absence of improvement in volitional walking, there were no adverse effects and the subjects found heel-switch triggered FES-assisted walking mostly "easy" (6 out of 7). Therefore FES is promising as an orthotic intervention for daily use; however, tailoring the intensity and/or frequency based on patient's ability may make it viable as a therapeutic intervention.

Background Nkx2.2 and Arx represent key transcription factors implicated in the specification of islet cell subtypes during pancreas development. Mice deficient for Arx do not develop any alpha-cells whereas beta- and delta-cells are found in considerably higher numbers. In Nkx2.2 mutant animals, alpha- and beta-cell development is severely impaired whereas a ghrelin-expressing cell population is found augmented. Notably, Arx transcription is clearly enhanced in Nkx2.2-deficient pancreata. Hence in order to precise the functional link between both factors we performed a comparative analysis of Nkx2.2/Arx single- and double-mutants but also of Pax6-deficient animals. Results We show that most of the ghrelin+ cells emerging in pancreata of Nkx2.2- and Pax6-deficient mice, express the alpha-cell specifier Arx, but also additional beta-cell related genes. In Nkx2.2-deficient mice, Arx directly co-localizes with iAPP, PC1/3 and Pdx1 suggesting an Nkx2.2-dependent control of Arx in committed beta-cells. The combined loss of Nkx2.2 and Arx likewise results in the formation of a hyperplastic ghrelin+ cell population at the expense of mature alpha- and beta-cells. Surprisingly, such Nkx2.2-/-Arx- ghrelin+ cells also express the somatostatin hormone. Conclusions Our data indicate that Nkx2.2 acts by reinforcing the transcriptional networks initiated by Pax4 and Arx in early committed beta- and alpha-cell, respectively. Our analysis also suggests that one of the coupled functions of Nkx2.2 and Pax4 is to counteract Arx gene activity in early committed beta-cells.

International audience; Functional Electrical Stimulation (FES) facilitates walking after paralysis by activating the muscles of the lower extremities. The FES-assisted stepping triggered either by a manual switch (switch-trigger), or by an electromyogram-based gait event detector (EMG-trigger) were presented in random order to two subjects with incomplete spinal cord injuries (iSCI) during ten trials over two alternate days. Subject iSCI-1 (C6 ASIA C) was non-ambulatory without the assistance of FES and could stand but not initiate a step volitionally. Subject iSCI-2 (T1 ASIA D) could walk only short distances with great difficulty without FES. Gait kinematics and kinetics were captured during FES-assisted over-ground walking with a rolling walker under laboratory conditions. Gait parameters including speed, left and right step length, left and right double support duration, left and right swing phase durations were extracted from the kinematic data. Mean, standard deviation, coefficient of variation, and 95% confidence interval were computed for each gait parameter under each triggering condition. The ground reaction forces were recorded for both the subjects while upper body support provided by the instrumented walker was recorded for iSCI-2. One way analysis of variance (ANOVA) was performed to determine whether significant differences existed in gait parameters between command sources. The left and right double support duration were significantly lower (p

International audience; Ambulation after spinal cord injury is possible with the aid of neuroprosthesis employing functional electrical stimulation (FES). Individuals with incomplete spinal cord injury (iSCI) retain partial volitional control of muscles below the level of injury, necessitating careful integration of FES with intact voluntary motor function for efficient walking. In this study, the intramuscular electromyogram (iEMG) was used to detect the intent to step and trigger FES-assisted walking in a volunteer with iSCI via an implanted neuroprosthesis consisting of two channels of bipolar iEMG signal acquisition and 12 independent channels of stimulation. The detection was performed with two types of classifiers- a threshold-based classifier that compared the running mean of the iEMG with a discrimination threshold to generate the trigger and a pattern recognition classifier that compared the time-history of the iEMG with a specified template of activity to generate the trigger whenever the cross-correlation coefficient exceeded a discrimination threshold. The pattern recognition classifier generally outperformed the threshold-based classifier, particularly with respect to minimizing False Positive triggers. The overall True Positive rates for the threshold-based classifier were 61.6% and 87.2% for the right and left steps with overall False Positive rates of 38.4% and 33.3%. The overall True Positive rates for the left and right step with the pattern recognition classifier were 57.2% and 93.3% and the overall False Positive rates were 11.9% and 24.4%. The subject showed no preference for either the threshold or pattern recognition-based classifier as determined by the Usability Rating Scale (URS) score collected after each trial and both the classifiers were perceived as moderately easy to use.

International audience; Functional electrical stimulation (FES) facilitates ambulatory function after paralysis by activating the muscles of the lower extremities. Individuals with incomplete spinal cord injury (iSCI) retain partial volitional control of muscles below the level of injury, necessitating careful integration of FES with intact voluntary motor function for efficient walking. The FES-assisted stepping can be triggered automatically at a fixed rate (autotrigger), by a manual switch (switch-trigger), or by an electromyogram-based gait-event-detector (EMG-trigger). It has been postulated that EMG may be a more natural command source than manual switches, and therefore will enable better coordination of stimulated and volitional motor functions necessary during gait. In this study, the above stated hypothesis was investigated in two volunteers with iSCI during the over-ground FES-assisted gait initiation. Four able-bodied volunteers provided the normative data for comparison. The EMG-triggered FES-assisted gait initiation was found to be more coordinated and dynamically more stable than autotriggered and switch-triggered cases. This highlighted the potential of surface EMG as a natural command interface to better coordinate stimulated and volitional muscle activities during gait.

International audience; The microchemical environment of neuromelanin (NM) in whole neurons from formalin fixed and paraffin embedded human substantia nigra sections were characterized using synchrotron chemical X-ray microscopy. Concentrations of NM-associated elements increased in the developing brain; the highest levels of most elements were found in the mature brain but the temporal pattern of the accumulation of different elements varied. High spatial resolution investigations, using a unique hard X-ray nanoprobe, revealed iron-rich microdomains colocalized with other elements within the pigment. These microdomains represent the first visualization of a structure regulating the metal-binding properties of NM and supporting a physiological role for NM in the regulation of functionally important elements in pigmented neurons. Our results demonstrate that the local chemical environment of iron in NM is similar to that found in ferritin and points to a possible role of iron in NM biosynthesis. Intracellular speciation of sulfur contained in NM revealed the presence of reduced sulfur compounds and various forms of oxidized sulfur compounds which have not previously been reported. Further, a significant increase in sulfonate in NM in the mature brain suggests that in vivo metabolism of the pigment via an as yet unidentified pathway occurs. The current data add to our understanding of the development and regulation of NM in the human brain.

International audience; Individuals with incomplete spinal cord injury (iSCI) retain some control of the partially paralyzed muscles, necessitating careful integration of functional electrical stimulation (FES) with intact motor function. In this communication, the volitional surface electromyogram (sEMG) from partially paralyzed muscle was used to detect the intent to step in an iSCI volunteer. The classifier was able to trigger the FES-assisted swing phase with a false positive rate less than 1% and true positive rate of 82% for left foot-off (FO) and 83% for right FO over 110 steps taken during three testing sessions spread over a week.

International audience; Ambulation after spinal cord injury is possible with the aid of functional electrical stimulation (FES). Individuals with incomplete spinal cord injury (iSCI) retain partial volitional control of muscles below the level of injury, necessitating careful integration of FES with intact voluntary motor function for efficient walking. In this study, the surface electromyogram (sEMG) of the volitionally controlled Erector Spinae was used to detect the intent to step and trigger FES-assisted walking in a volunteer with iSCI via 8-channel implanted stimulation system. The inference system was able to trigger the FES-assisted swing-phase of gait with a false positive rate of 1% during over ground ambulation on a level surface. The performance of the sEMG inference system highlights its potential as a natural command interface to better coordinate stimulated and volitional muscle activities than conventional manual switches and facilitate FES-assisted community ambulation.

International audience; Functional electrical stimulation (FES) facilitates ambulatory function after paralysis of persons with spinal cord injury (SCI) by exciting the peripheral motor nerves to activate the muscles of the lower limbs. This study identified a process for selecting command sources for triggering FES with the surface electromyogram (EMG) from muscles partially paralyzed by incomplete SCI, given its high degree of intersubject variability. We found Discriminability Index (DI) to be a good metric to evaluate the potential of controlling FES-assisted ambulation in four nondisabled volunteers and two participants with incomplete paralysis. The left erector spinae (ES) (mean DI = 0.87) for triggering the left step and the right ES (mean DI = 0.83) for triggering the right step were the best command sources for participant 1. The left ES (mean DI = 0.93) for triggering the left step and the right medial gastrocnemius (mean DI = 0.88) for triggering the right step were the best command sources for participant 2. Our results showed that command sources can be selected objectively from surface EMG before a fully implantable EMG-triggered FES system for walking is implemented.

International audience; BackgroundFunctional Electrical Stimulation (FES) can electrically activate paretic muscles to assist movement for post-stroke neurorehabilitation. Here, sensory-motor integration may be facilitated by triggering FES with residual electromyographic (EMG) activity. However, muscle activity following stroke often suffers from delays in initiation and termination which may be alleviated with an adjuvant treatment at the central nervous system (CNS) level with transcranial direct current stimulation (tDCS) thereby facilitating re-learning and retaining of normative muscle activation patterns.MethodsThis study on 12 healthy volunteers was conducted to investigate the effects of anodal tDCS of the primary motor cortex (M1) and cerebellum on latencies during isometric contraction of tibialis anterior (TA) muscle for myoelectric visual pursuit with quick initiation/termination of muscle activation i.e. 'ballistic EMG control' as well as modulation of EMG for 'proportional EMG control'.ResultsThe normalized delay in initiation and termination of muscle activity during post-intervention 'ballistic EMG control' trials showed a significant main effect of the anodal tDCS target: cerebellar, M1, sham (F(2) = 2.33, p < 0.1), and interaction effect between tDCS target and step-response type: initiation/termination of muscle activation (F(2) = 62.75, p < 0.001), but no significant effect for the step-response type (F(1) = 0.03, p = 0.87). The post-intervention population marginal means during 'ballistic EMG control' showed two important findings at 95% confidence interval (critical values from Scheffe's S procedure): 1. Offline cerebellar anodal tDCS increased the delay in initiation of TA contraction while M1 anodal tDCS decreased the same when compared to sham tDCS, 2. Offline M1 anodal tDCS increased the delay in termination of TA contraction when compared to cerebellar anodal tDCS or sham tDCS. Moreover, online cerebellar anodal tDCS decreased the learning rate during 'proportional EMG control' when compared to M1 anodal and sham tDCS.ConclusionsThe preliminary results from healthy subjects showed specific, and at least partially antagonistic effects, of M1 and cerebellar anodal tDCS on motor performance during myoelectric control. These results are encouraging, but further studies are necessary to better define how tDCS over particular regions of the cerebellum may facilitate learning of myoelectric control for brain machine interfaces.