Search

IntroductionEncouraging the activation of brain repair mechanisms and fostering spontaneous functional recovery in stroke patients hold great promise for alleviating the global burden of this condition and allowing an extended therapeutic time window. Cell-based regenerative therapy (with mesenchymal stem/stromal cells, such as adipose-derived stem cells [ADSCs]) is particularly attractive considering its excellent safety profile, low immunogenicity after allogeneic application, and well-established functional benefits on stroke recovery in animal models. This study aims to assess the efficacy and safety effects of intravenous (IV) infusion of freshly cultured allogeneic ADSCs on recovery after ischemic stroke.Population and methodsRESSTORE is a multicentric, randomized 1:1 controlled double-blind clinical trial. Eighty patients will be enrolled in nine French stroke centers. The main inclusion criteria are ≥18 years of age, acute hemispheric ischemic stroke, and a National Institutes of Health Stroke Scale (NIHSS) score of ≥7, including a motor subscore of ≥3. According to the previous dose-escalation safety trial data, the maximum tolerated dose of 3 million ADSCs/kg was selected. IV infusion was performed within 10 days following stroke onset, with a follow-up over 2 years.OutcomesThe primary endpoint is the motor NIHSS subscore, computed as the sum of the upper limb, lower limb, and hand scores, measured 6 months after stroke onset to assess motor recovery. The secondary outcomes are the occurrence of death/serious adverse events, clinical scores (the detailed NIHSS scores, Montreal Cognitive Assessment scores, modified Rankin Scale scores, Aphasia Handicap Scores, Depression Intensity Scale Circles scores, Fatigue Scale scores, etc.), immune monitoring (for the first 30 patients), and multimodal biomarkers derived from diffusion and functional magnetic resonance imaging.DiscussionThis study may provide some evidence for the effects of freshly cultured allogenic ADSCs IV infusion in subacute stroke that may help design a larger international randomized controlled trial.

BackgroundDisconnected consciousness describes a state in which subjective experience (i.e., consciousness) becomes isolated from the external world. It appears frequently during sleep or sedation, when subjective experiences remain vivid but are unaffected by external stimuli. Traditional methods of differentiating connected and disconnected consciousness, such as relying on behavioral responsiveness or on post-anesthesia reports, have demonstrated limited accuracy: unresponsiveness has been shown to not necessarily equate to unconsciousness and amnesic effects of anesthesia and sleep can impair explicit recollection of events occurred during sleep/sedation. Due to these methodological challenges, our understanding of the neural mechanisms underlying sensory disconnection remains limited.MethodsTo overcome these methodological challenges, we employ a distinctive strategy by combining a serial awakening paradigm with auditory stimulation during mild propofol sedation. While under sedation, participants are systematically exposed to auditory stimuli and questioned about their subjective experience (to assess consciousness) and their awareness of the sounds (to evaluate connectedness/disconnectedness from the environment). The data collected through interviews are used to categorize participants into connected and disconnected consciousness states. This method circumvents the requirement for responsiveness in assessing consciousness and mitigates amnesic effects of anesthesia as participants are questioned while still under sedation. Functional MRI data are concurrently collected to investigate cerebral activity patterns during connected and disconnected states, to elucidate sensory disconnection neural gating mechanisms. We examine whether this gating mechanism resides at the thalamic level or results from disruptions in information propagation to higher cortices. Furthermore, we explore the potential role of slow-wave activity (SWA) in inducing disconnected consciousness by quantifying high-frequency BOLD oscillations, a known correlate of slow-wave activity.DiscussionThis study represents a notable advancement in the investigation of sensory disconnection. The serial awakening paradigm effectively mitigates amnesic effects by collecting reports immediately after regaining responsiveness, while still under sedation. Ultimately, this research holds the potential to understand how sensory gating is achieved at the neural level. These biomarkers might be relevant for the development of sensitive anesthesia monitoring to avoid intraoperative connected consciousness and for the assessment of patients suffering from pathologically reduced consciousness.Clinical trial registrationEuropean Union Drug Regulating Authorities Clinical Trials Database (EudraCT), identifier 2020-003524-17.

Abstract Exposure to blue wavelength light stimulates alertness and performance by modulating a widespread set of task-dependent cortical and subcortical areas. How light affects the crosstalk between brain areas to trigger this stimulating effect is not established. Here we record the brain activity of 19 healthy young participants (24.05±2.63; 12 women) while they complete an auditory attentional task in darkness or under an active (blue-enriched) or a control (orange) light, in an ultra-high-field 7 Tesla MRI scanner. We test if light modulates the effective connectivity between an area of the posterior associative thalamus, encompassing the pulvinar, and the intraparietal sulcus (IPS), key areas in the regulation of attention. We find that only the blue-enriched light strengthens the connection from the posterior thalamus to the IPS. To the best of our knowledge, our results provide the first empirical data supporting that blue wavelength light affects ongoing non-visual cognitive activity by modulating task-dependent information flow from subcortical to cortical areas.

Abstract Background In parallel to the traditional symptomatology, deficits in cognition (memory, attention, reasoning, social functioning) contribute significantly to disability and suffering in individuals with schizophrenia. Cognitive deficits have been closely linked to alterations in early auditory processes (EAP) that occur in auditory cortical areas. Preliminary evidence indicates that cognitive deficits in schizophrenia can be improved with a reliable and safe non-invasive brain stimulation technique called tDCS (transcranial direct current stimulation). However, a significant proportion of patients derive no cognitive benefits after tDCS treatment. Furthermore, the neurobiological mechanisms of cognitive changes after tDCS have been poorly explored in trials and are thus still unclear. Method The study is designed as a randomized, double-blind, 2-arm parallel-group, sham-controlled, multicenter trial. Sixty participants with recent-onset schizophrenia and cognitive impairment will be randomly allocated to receive either active (n=30) or sham (n=30) tDCS (20-min, 2-mA, 10 sessions during 5 consecutive weekdays). The anode will be placed over the left dorsolateral prefrontal cortex and the cathode over the left auditory cortex. Cognition, tolerance, symptoms, general outcome and EAP (measured with EEG and multimodal MRI) will be assessed prior to tDCS (baseline), after the 10 sessions, and at 1- and 3-month follow-up. The primary outcome will be the number of responders, defined as participants demonstrating a cognitive improvement ≥Z=0.5 from baseline on the MATRICS Consensus Cognitive Battery total score at 1-month follow-up. Additionally, we will measure how differences in EAP modulate individual cognitive benefits from active tDCS and whether there are changes in EAP measures in responders after active tDCS. Discussion Besides proposing a new fronto-temporal tDCS protocol by targeting the auditory cortical areas, we aim to conduct a randomized controlled trial (RCT) with follow-up assessments up to 3 months. In addition, this study will allow identifying and assessing the value of a wide range of neurobiological EAP measures for predicting and explaining cognitive deficit improvement after tDCS. The results of this trial will constitute a step toward the use of tDCS as a therapeutic tool for the treatment of cognitive impairment in recent-onset schizophrenia. Trial registration ClinicalTrials.gov NCT05440955. Prospectively registered on July 1st, 2022.

BACKGROUND The locus coeruleus (LC) is the primary source of norepinephrine in the brain and regulates arousal and sleep. Animal research shows that it plays important roles in the transition between sleep and wakefulness, and between slow wave sleep and rapid eye movement sleep (REMS). It is unclear, however, whether the activity of the LC predicts sleep variability in humans.METHODS We used 7-Tesla functional MRI, sleep electroencephalography (EEG), and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 33 healthy younger (~22 years old; 28 women, 5 men) and 19 older (~61 years old; 14 women, 5 men) individuals.RESULTS We found that, in older but not in younger participants, higher LC activity, as probed during an auditory attentional task, was associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS. The results remained robust even when accounting for the age-related changes in the integrity of the LC.CONCLUSION These findings suggest that LC activity correlates with the perception of the sleep quality and an essential oscillatory mode of REMS, and we found that the LC may be an important target in the treatment of sleep- and age-related diseases.FUNDING This work was supported by Fonds National de la Recherche Scientifique (FRS-FNRS, T.0242.19 & J. 0222.20), Action de Recherche Concertée – Fédération Wallonie-Bruxelles (ARC SLEEPDEM 17/27-09), Fondation Recherche Alzheimer (SAO-FRA 2019/0025), ULiège, and European Regional Development Fund (Radiomed & Biomed-Hub).

IntroductionThe brainstem locus coeruleus (LC) influences a broad range of brain processes, including cognition. The so-called LC contrast is an accepted marker of the integrity of the LC that consists of a local hyperintensity on specific Magnetic Resonance Imaging (MRI) structural images. The small size of the LC has, however, rendered its functional characterization difficult in humans, including in aging. A full characterization of the structural and functional characteristics of the LC in healthy young and late middle-aged individuals is needed to determine the potential roles of the LC in different medical conditions. Here, we wanted to determine whether the activation of the LC in a mismatch negativity task changes in aging and whether the LC functional response was associated to the LC contrast.MethodsWe used Ultra-High Field (UHF) 7-Tesla functional MRI (fMRI) to record brain response during an auditory oddball task in 53 healthy volunteers, including 34 younger (age: 22.15y ± 3.27; 29 women) and 19 late middle-aged (age: 61.05y ± 5.3; 14 women) individuals.ResultsWhole-brain analyses confirmed brain responses in the typical cortical and subcortical regions previously associated with mismatch negativity. When focusing on the brainstem, we found a significant response in the rostral part of the LC probability mask generated based on individual LC images. Although bilateral, the activation was more extensive in the left LC. Individual LC activity was not significantly different between young and late middle-aged individuals. Importantly, while the LC contrast was higher in older individuals, the functional response of the LC was not significantly associated with its contrast.DiscussionThese findings may suggest that the age-related alterations of the LC structural integrity may not be related to changes in its functional response. The results further suggest that LC responses may remain stable in healthy individuals aged 20 to 70.

Midplane gas puffing close to the ion cyclotron range of frequencies (ICRF) antennae has been demonstrated to be robust in improving ICRF power coupling in current tokamaks. It is also shown in a previous study (Zhang 2019 Nucl. Mater. Energy 19 364–71) that in ITER, midplane gas puffing with a puff rate of ∼4.5 × 10 ^22 electrons s ^−1 can increase the antenna loading/coupling resistance by about a factor of two. In this paper, a comprehensive parametric study has been carried out to characterize the influence of midplane gas puffing on ICRF power coupling in additional and broader range of parameter scans. The new parameter scans include the gas puff rate, the poloidal location of the gas pipe orifices (GPOs), the separatrix density, the particle perpendicular diffusion coefficient, the radial distance between the plasma and antenna as well as the antenna phasing. The 3D edge plasma fluid and neutral transport code EMC3-EIRENE code has been used to simulate the 3D distributions of plasma density in the presence of gas puffing, which are then used in the antenna code ANTITER II to calculate the antenna coupling. The simulation results indicate that the ITER ICRF local midplane gas injection layout (with the GPOs located on one side of each antenna port) increases the ICRF power coupling significantly in all studied plasma scenarios and antenna parameters. We are hence confident that the chosen layout for the ICRF local gas injection on ITER is appropriate. We are also confident that the ITER local gas injection will allow boosting the ICRF coupling with all studied plasma conditions and antenna phasings.

This paper documents the analysis of the ITER ion cyclotron resonance heating (ICRF) launcher using the TOPICA code, throughout recent years’ design activities. The ability to simulate the detailed geometry of an ICRF antenna in front of a realistic plasma and to obtain the antenna input parameters, the electric currents on conductors and the radiated field distribution next to the antenna is of significant importance to evaluate and predict the overall system performances. Starting from a reference geometry, we first investigated the impact of some geometrical and numerical factors, such as the Faraday Screen geometry or the mesh quality. Then a final geometry was the object of a comprehensive analysis, varying the working frequency, the plasma conditions and the poloidal and toroidal phasings between the feeding lines. The performance of the antenna has been documented in terms of input parameters, power coupled to plasma and electric fields. Eventually, the four-port junction has also been included in TOPICA models.

Deep learning-based convolutional neural networks have recently proved their efficiency in providing fast segmentation of major brain fascicles structures, based on diffusion-weighted imaging. The quantitative analysis of brain fascicles then relies on metrics either coming from the tractography process itself or from each voxel along the bundle.Statistical detection of abnormal voxels in the context of disease usually relies on univariate and multivariate statistics models, such as the General Linear Model (GLM). Yet in the case of high-dimensional low sample size data, the GLM often implies high standard deviation range in controls due to anatomical variability, despite the commonly used smoothing process. This can lead to difficulties to detect subtle quantitative alterations from a brain bundle at the voxel scale.Here we introduce TractLearn, a unified framework for brain fascicles quantitative analyses by using geodesic learning as a data-driven learning task. TractLearn allows a mapping between the image high-dimensional domain and the reduced latent space of brain fascicles using a Riemannian approach.We illustrate the robustness of this method on a healthy population with test-retest acquisition of multi-shell diffusion MRI data, demonstrating that it is possible to separately study the global effect due to different MRI sessions from the effect of local bundle alterations. We have then tested the efficiency of our algorithm on a sample of 5 age-matched subjects referred with mild traumatic brain injury.Our contributions are to propose:1/ A manifold approach to capture controls variability as standard reference instead of an atlas approach based on a Euclidean mean.2/ A tool to detect global variation of voxels’ quantitative values, which accounts for voxels’ interactions in a structure rather than analyzing voxels independently.3/ A ready-to-plug algorithm to highlight nonlinear variation of diffusion MRI metrics.With this regard, TractLearn is a ready-to-use algorithm for precision medicine.

Ion cyclotron resonance heating (ICRH) is one of the three additional heating schemes to be deployed on ITER. Its two antenna arrays, installed on the outboard midplane, will deliver 20 MW of RF power in the 40–55 MHz frequency range. The plasma-facing component of the antenna assembly is the Faraday screen, comprising beryllium (Be) tile armoured, actively cooled bars located only ~1 cm radially behind the innermost point of the shaped Be first wall panels (FWPs). As such they are in close proximity to the scrape-off layer (SOL) plasma and it is important to assess the maximum heat loads that the screen bars may experience during high power ITER operation. This paper provides a detailed assessment of these loads using the new 3D field line tracing and power deposition framework SMITER (Kos et al., 2019). The focus is on the H-mode, burning plasma scenario, taking into account both plasma heat loading (including average loading due to mitigated Type I ELMs) and the loads due to photonic impact (assessed with the optical ray-tracing package Raysect (Meakins and Carr, 2017)) from power radiated in the core obtained from integrated JINTRAC simulations. Calculations are also performed to assess the minimum allowed antenna to magnetic separatrix distances, for cases in which closer approach may be required to improve RF coupling.

Current theoretical frameworks suggest that human behaviors are based on strong and complex interactions between cognitive processes such as those underlying language and memory functions in normal and neurological populations. We were interested in assessing the dynamic cerebral substrate of such interaction between language and declarative memory, as the composite function, in healthy controls (HC, N = 19) and patients with temporal lobe epilepsy (TLE, N = 16). Our assumption was that the language and declarative memory integration is based on a language-and-memory network (LMN) that is dynamic and reconfigures according to task demands and brain status. Therefore, we explored two types of LMN dynamics, a state reconfiguration (intrinsic resting-state compared to extrinsic state assessed with a sentence recall task) and a reorganization of state reconfiguration (TLE compared to HC). The dynamics was evaluated in terms of segregation (community or module detection) and integration (connector hubs). In HC, the level of segregation was the same in both states and the mechanism of LMN state reconfiguration was shown through module change of key language and declarative memory regions with integrative roles. In TLE patients, the reorganization of LMN state reconfiguration was reflected in segregation increase and extrinsic modules that were based on shorter-distance connections. While lateral and mesial temporal regions enabled state reconfiguration in HC, these regions showed reduced flexibility in TLE. We discuss our results in a connectomic perspective and propose a dynamic model of language and declarative memory functioning. We claim that complex and interactive cognitive functions, such as language and declarative memory, should be investigated dynamically, considering the interaction between cognitive networks.

While motor recovery following mild stroke has been extensively studied with neuroimaging, mechanisms of recovery after moderate to severe strokes of the types that are often the focus for novel restorative therapies remain obscure. We used fMRI to: 1) characterize reorganization occurring after moderate to severe subacute stroke, 2) identify brain regions associated with motor recovery and 3) to test whether brain activity associated with passive movement measured in the subacute period could predict motor outcome six months later. Because many patients with large strokes involving sensorimotor regions cannot engage in voluntary movement, we used passive flexion-extension of the paretic wrist to compare 21 patients with subacute ischemic stroke to 24 healthy controls one month after stroke. Clinical motor outcome was assessed with Fugl-Meyer motor scores (motor-FMS) six months later. Multiple regression, with predictors including baseline (one-month) motor-FMS and sensorimotor network regional activity (ROI) measures, was used to determine optimal variable selection for motor outcome prediction. Sensorimotor network ROIs were derived from a meta-analysis of arm voluntary movement tasks. Bootstrapping with 1000 replications was used for internal model validation. During passive movement, both control and patient groups exhibited activity increases in multiple bilateral sensorimotor network regions, including the primary motor (MI), premotor and supplementary motor areas (SMA), cerebellar cortex, putamen, thalamus, insula, Brodmann area (BA) 44 and parietal operculum (OP1-OP4). Compared to controls, patients showed: 1) lower task-related activity in ipsilesional MI, SMA and contralesional cerebellum (lobules V-VI) and 2) higher activity in contralesional MI, superior temporal gyrus and OP1-OP4. Using multiple regression, we found that the combination of baseline motor-FMS, activity in ipsilesional MI (BA4a), putamen and ipsilesional OP1 predicted motor outcome measured 6 months later (adjusted-R2 = 0.85; bootstrap p

Objective. Hypoxic exposure in healthy subjects can induce acute mountain sickness including headache, lethargy, cerebral dysfunction and substantial cerebral structural alterations which, in worst case, can lead to potentially fatal high altitude cerebral edema. Within this context, the relationships between high altitude-induced cerebral edema, changes in cerebral perfusion, increased brain parenchyma volume, increased intracranial pressure and symptoms remain unclear. Methods. In 11 subjects before and after 6 days at 4,350 m, we performed multiparametric magnetic resonance investigations including anatomical, apparent diffusion coefficient and arterial spin labelling sequences. Results. After the altitude stay, while subjects were asymptomatic, white matter volume (+0.7±0.4%, p=0.005), diffusion (+1.7±1.4%, p=0.002) and cerebral blood flow (+28±38%; p=0.036) were significantly increased while cerebrospinal fluid volume was reduced (-1.4±1.1%, p=0.009). Optic nerve sheath diameter (used as an index of increased intracranial pressure) was unchanged from before (5.84±0.53 mm) to after (5.92±0.60 mm, p=0.390) altitude exposure. Correlations were observed between increases in white matter volume and diffusion (rho=0.81, p=0.016) and between changes in cerebrospinal fluid volume and changes in optic nerve sheath diameters (rho=-0.92, p=0.006) and symptoms during the altitude stay (rho=-0.67, p=0.031). Conclusions. These data demonstrate white matter alterations after several days at high altitude when subjects are asymptomatic that may represent the normal brain response to prolonged high altitude exposure.

ITER plasma operation requires a non-active phase for tokamak initial commissioning, covering First Plasma and Pre-Fusion Power Operation phases, PFPO-1 and PFPO-2. Non-active operation consists of hydrogen and helium plasmas to minimize the neutron production rate. The present document describes some Ion Cyclotron Radio Frequency (ICRF) heating schemes in terms of their predicted performance for the main foreseen scenarios of the ITER non-active phase in hydrogen and helium. Emphasis is given on remaining issues and physics uncertainties to be addressed for successful ICRF heating in ITER.

Recent studies have provided evidence for sensory-motor adaptive changes and action goal coding of visually guided manual action in premotor and posterior parietal cortices. To extend these results to orofacial actions, devoid of auditory and visual feedback, we used a repetition suppression paradigm while measuring neural activity with functional magnetic resonance imaging during repeated intransitive and silent lip, jaw and tongue movements. In the motor domain, this paradigm refers to decreased activity in specific neural populations due to repeated motor acts and has been proposed to reflect sensory-motor adaptation. Orofacial movements activated a set of largely overlapping, common brain areas forming a core neural network classically involved in orofacial motor control. Crucially, suppressed neural responses during repeated orofacial actions were specifically observed in the left ventral premotor cortex, the intraparietal sulcus, the inferior parietal lobule and the superior parietal lobule. Since no visual and auditory feedback were provided during orofacial actions, these results suggest somatosensory-motor adaptive control of intransitive and silent orofacial actions in these premotor and parietal regions.

The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and by regulating endothelial cell survival and migration. Protease system's role in lymphangiogenesis is unknown yet. Thus, based on its important pro-angiogenic effect, we hypothesized that PAI-1 may regulate lymphangiogenesis associated at least with metastatic dissemination of cancer cells. To address this issue, we studied the impact of PAI-1 deficiency in various murine models of tumoral lymphangiogenesis. Wild-type PAI-1 proficient mice were used as controls. We provide for the first time evidence that PAI-1 is dispensable for tumoral lymphangiogenesis associated with breast cancers either induced by mammary carcinoma cell injection or spontaneously appearing in transgenic mice expressing the polyomavirus middle T antigen (PymT) under the control of a mouse mammary tumor virus long-terminal repeat promoter (MMTV-LTR). We also investigated inflammation-related lymphatic vessel recruitment by using two inflammatory models. PAI-1 deficiency did neither affect the development of lymphangioma nor burn-induced corneal lymphangiogenesis. These novel data suggest that vascular remodelling associated with lymphangiogenesis and angiogenesis involve different molecular determinants. PAI-1 does not appear as a potential therapeutic target to counteract pathological lymphangiogenesis.