MRI-based microthrombi detection in stroke with polydopamine iron oxide.

In acute ischemic stroke, even when successful recanalization is obtained, downstream microcirculation may still be obstructed by microvascular thrombosis, which is associated with compromised brain reperfusion and cognitive decline. Identifying these microthrombi through non-invasive methods remains challenging. We developed the PHySIOMIC (Polydopamine Hybridized Self-assembled Iron Oxide Mussel Inspired Clusters), a MRI-based contrast agent that unmasks these microthrombi. In a mouse model of thromboembolic ischemic stroke, our findings demonstrate that the PHySIOMIC generate a distinct hypointense signal on T2*-weighted MRI in the presence of microthrombi, that correlates with the lesion areas observed 24 hours post-stroke. Our microfluidic studies reveal the role of fibrinogen in the protein corona for the thrombosis targeting properties. Finally, we observe the biodegradation and biocompatibility of these particles. This work demonstrates that the PHySIOMIC particles offer an innovative and valuable tool for non-invasive in vivo diagnosis and monitoring of microthrombi, using MRI during ischemic stroke.

The multiscale topological organization of the functional brain network in adolescent PTSD.

The experience of an extremely aversive event can produce enduring deleterious behavioral, and neural consequences, among which posttraumatic stress disorder (PTSD) is a representative example. Although adolescence is a period of great exposure to potentially traumatic events, the effects of trauma during adolescence remain understudied in clinical neuroscience. In this exploratory work, we aim to study the whole-cortex functional organization of 14 adolescents with PTSD using a data-driven method tailored to our population of interest. To do so, we built on the network neuroscience framework and specifically on multilayer (multisubject) community analysis to study the functional connectivity of the brain. We show, across different topological scales (the number of communities composing the cortex), a hyper-colocalization between regions belonging to occipital and pericentral regions and hypo-colocalization in middle temporal, posterior-anterior medial, and frontal cortices in the adolescent PTSD group compared to a nontrauma exposed group of adolescents. These preliminary results raise the question of an altered large-scale cortical organization in adolescent PTSD, opening an interesting line of research for future investigations.

Physical Activity Attenuates Brain Irradiation-Associated Skeletal Muscle Damage in the Rat.

PURPOSE: Radiation therapy for brain tumors increases patient survival. Nonetheless, side effects are increasingly reported such as cognitive deficits and fatigue. The etiology of fatigue remains poorly described. Our hypothesis is that the abscopal effects of radiation therapy on skeletal muscle may be involved in fatigue. The present study aims to assess the effect of brain irradiation on skeletal muscles and its relationship with fatigue and to analyze whether physical activity could counteract brain radiation-induced side effects. METHODS AND MATERIALS: Adult Wistar rats were randomly distributed between 4 groups: control (CTL), irradiated (IR), nonirradiated with physical activity (PA), and irradiated with physical activity (IR+PA). IR rats were exposed to a whole-brain irradiation (WBI) of 30 Gy (3 × 10 Gy). Rats subjected to PA underwent sessions of running on a treadmill, 3 times/week for 6 months. The effects of WBI on muscles were evaluated by complementary approaches: behavioral tests (fatigue, locomotion activity), magnetic resonance imaging, and histologic analyses. RESULTS: IR rats displayed a significant fatigue and a reduced locomotor activity at short term compared with the CTL group, which were attenuated with PA at 6 months after WBI. The IR rat's gastrocnemius mass decreased compared with CTL rats, which was reversed by physical activity at 14 days after WBI. Multiparametric magnetic resonance imaging of the skeletal muscle highlighted an alteration of the fiber organization in IR rats as demonstrated by a significant decrease of the mean diffusivity in the gastrocnemius at short term. Alteration of fibers was confirmed by histologic analyses: the number of type I fibers was decreased, whereas that of type IIa fibers was increased in IR animals but not in the IR+PA group. CONCLUSIONS: The data show that WBI induces skeletal muscle damage, which is attenuated by PA. This muscle damage may explain, at least in part, the fatigue of patients treated with radiation therapy.

Autobiographical Cerebral Network Activation in Older Adults Before and After Reminiscence Therapy: A Preliminary Report.

INTRODUCTION: Reminiscence therapy (RT), which engages individuals to evoke positive memories, has been shown to be effective in improving psychological well-being in older adults suffering from PTSD, depression, and anxiety. However, its impact on brain function has yet to be determined. This paper presents functional magnetic resonance imaging (fMRI) data to describe changes in autobiographical memory networks (AMN) in community-dwelling older adults. METHODS: This pilot study used a within-subject design to measure changes in AMN activation in 11 older adults who underwent 6 weeks of RT. In the scanner, participants retrieved autobiographical memories which were either recent or remote, rehearsed or unrehearsed. Participants also underwent a clinical interview to assess changes in memory, quality of life, mental health, and affect. FINDINGS: Compared to pretreatment, anxiety decreased (z = -2.014, p = .040) and activated significant areas within the AMN, including bilateral medial prefrontal cortex, left precuneus, right occipital cortex, and left anterior hippocampus. CONCLUSION: Although RT had subtle effects on psychological function in this sample with no evidence of impairments, including depression at baseline, the fMRI data support current thinking of the effect RT has on the AMN. Increased activation of right posterior hippocampus following RT is compatible with the Multiple Trace Theory Theory (Nadel & Moscovitch, 1997).

Effects of sleep disturbances and circadian rhythms modifications on cognition in breast cancer women before and after adjuvant chemotherapy: the ICANSLEEP-1 protocol.

BACKGROUND: Many patients treated for breast cancer (BC) complain about cognitive difficulties affecting their daily lives. Recently, sleep disturbances and circadian rhythm disruptions have been brought to the fore as potential contributors to cognitive difficulties in patients with BC. Yet, studies on these factors as well as their neural correlates are scarce. The purpose of the ICANSLEEP-1 (Impact of SLEEP disturbances in CANcer) study is to characterize sleep using polysomnography and its relationship with the evolution of cognitive functioning at both the behavioral and the neuroanatomical levels across treatment in BC patients treated or not with adjuvant chemotherapy. METHODS: ICANSLEEP-1 is a longitudinal study including BC patients treated with adjuvant chemotherapy (n = 25) or not treated with adjuvant chemotherapy (n = 25) and healthy controls with no history of BC (n = 25) matched for age (45-65 years old) and education level. The evaluations will take place within 6 weeks after inclusion, before the initiation of chemotherapy (for BC patients who are candidates for chemotherapy) or before the first fraction of radiotherapy (for BC patients with no indication for chemotherapy) and 6 months later (corresponding to 2 weeks after the end of chemotherapy). Episodic memory, executive functions, psychological factors, and quality of life will be assessed with validated neuropsychological tests and self-questionnaires. Sleep quantity and quality will be assessed with polysomnography and circadian rhythms with both actigraphy and saliva cortisol. Grey and white matter volumes, as well as white matter microstructural integrity, will be compared across time between patients and controls and will serve to further investigate the relationship between sleep disturbances and cognitive decline. DISCUSSION: Our results will help patients and clinicians to better understand sleep disturbances in BC and their relationship with cognitive functioning across treatment. This will aid the identification of more appropriate sleep therapeutic approaches adapted to BC patients. Improving sleep in BC would eventually help limit cognitive deficits and thus improve quality of life during and after treatments. TRIAL REGISTRATION: NCT05414357, registered June 10, 2022. PROTOCOL VERSION: Version 1.2 dated March 23, 2022.

Grey matter volume and CSF biomarkers predict neuropsychological subtypes of MCI.

There is increasing evidence of different subtypes of individuals with mild cognitive impairment (MCI). An important line of research is whether neuropsychologically-defined subtypes have distinct patterns of neurodegeneration and cerebrospinal fluid (CSF) biomarker composition. In our study, we demonstrated that MCI participants of the ADNI database (N = 640) can be discriminated into 3 coherent neuropsychological subgroups. Our clustering approach revealed amnestic MCI, mixed MCI, and cluster-derived normal subgroups. Furthermore, classification modeling revealed that specific predictive features can be used to differentiate amnestic and mixed MCI from cognitively normal (CN) controls: CSF Aß142 concentration for the former and CSF Aß1-42 concentration, tau concentration as well as grey matter atrophy (especially in the temporal and occipital lobes) for the latter. In contrast, participants from the cluster-derived normal subgroup exhibited an identical profile to CN controls in terms of cognitive performance, brain structure, and CSF biomarker levels. Our comprehensive data analytics strategy provides further evidence that multimodal neuropsychological subtyping is both clinically and neurobiologically meaningful.

Consequences of General Anesthesia in Infancy on Behavior and Brain Structure.

BACKGROUND: One in 7 children will need general anesthesia (GA) before the age of 3. Brain toxicity of anesthetics is controversial. Our objective was to clarify whether exposure of GA to the developing brain could lead to lasting behavioral and structural brain changes. METHODS: A first study was performed in mice. The behaviors (fear conditioning, Y-maze, and actimetry) and brain anatomy (high-resolution magnetic resonance imaging) of 6- to 8-week-old Swiss mice exposed or not exposed to GA from 4 to 10 days old were evaluated. A second study was a complementary analysis from the preexisting APprentissages EXécutifs et cerveau chez les enfants d'âge scolaire (APEX) cohort to assess the replicability of our data in humans. The behaviors (behavior rating inventory of executive function, emotional control, and working memory score, Backward Digit Span, and Raven 36) and brain anatomy (high-resolution magnetic resonance imaging) were compared in 102 children 9 to 10 years of age exposed or not exposed to a single GA (surgery) during infancy. RESULTS: The animal study revealed chronic exacerbated fear behavior in the adult mice (95% confidence interval [CI], 4-80; P = .03) exposed to postnatal GA; this was associated with an 11% (95% CI, 7.5-14.5) reduction of the periaqueductal gray matter (P = .046). The study in humans suggested lower emotional control (95% CI, 0.33-9.10; P = .06) and a 6.1% (95% CI, 4.3-7.8) reduction in the posterior part of the right inferior frontal gyrus (P = .019) in the children who had been exposed to a single GA procedure. CONCLUSIONS: The preclinical and clinical findings of these independent studies suggest lasting effects of early life exposure to anesthetics on later emotional control behaviors and brain structures.

Approach in green, avoid in red? Examining interindividual variabilities and personal color preferences through continuous measures of specific meaning associations.

Empirically based literature suggests that avoidance/approach motivation arising from color-meaning associations assume a key mediational role in the color effect during psychological functioning. Even if several studies investigated color-meaning associations through different methodological approaches, no study investigated specific color-meaning associations (1) through continuous measures (2) for both positive and negative meanings. In addition, color effects are not unequivocal, and interindividual variability issues are still underexplored. The present study is based on the application of visual analog scales to assess continuous measures of specific color-meaning associations related to both negative and positive meanings that could rely on avoidance/approach motivation. The data analyses compared the distribution of the color-meaning association scores rated by participants (N = 152) on visual analog scales. The results showed strong associations between red color and items that could be related to avoidance motivation. Conversely, green color association scores showed distinct and specific associations that could be related to approach motivation. The results also revealed that blue color could exhibit a similar pattern for some meaning association scores compared with green color, as well as orange compared with red association scores. In addition, the results suggest that color preferences may influence color effects, especially regarding color-related approach motivation. The present study provides new insights about the color effect on psychological functioning and a novel approach to investigate the mediational processes such as avoidance/approach motivation that considers interindividual differences along a continuum.

Functional connectivity correlates of attentional networks in insomnia disorder: A pilot study.

Insomnia disorder has been associated with poor executive functioning. Functional imaging studies of executive functioning in insomnia are scarce and inconclusive. Because the Attentional Network Test relies on well-defined cortical networks and sensitively distinguishes different aspects of executive function, it might reveal brain functional alterations in relatively small samples of patients. The current pilot study assessed functional connectivity during the Attentional Network Test performed using magnetic resonance imaging in 12 participants with insomnia and 13 self-defined good sleepers. ANCOVAs were used to evaluate group differences in performance and functional connectivity in the regions of interest representing the attentional networks (i.e. alerting, orienting and executive control) at p < 0.05, uncorrected. During the orienting part, participants with insomnia showed weaker connectivity of the precentral gyrus with the superior parietal lobe (false discovery rate-corrected), while they showed stronger connectivity between premotor and visual regions. Individual differences in connectivity between premotor and visual regions correlated inversely with reaction time. Reaction times suggested more efficient executive control in participants with insomnia compared with good sleepers. During the executive control part, participants with insomnia showed stronger connectivity of thalamic parts of the arousal circuit with the middle frontal and the occipital gyri. Conversely, connectivity between the inferior and superior frontal gyri was weaker. Participants with insomnia seem to recruit more cortical resources in visuo-motor regions to orient attention than good sleepers do, and seem to have enhanced executive control that relates to stronger connectivity of arousal-related thalamic areas. This latter result should be treated with caution and requires confirmation.

Tracking the immune response by MRI using biodegradable and ultrasensitive microprobes.

Molecular magnetic resonance imaging (MRI) holds great promise for diagnosis and therapeutic monitoring in a wide range of diseases. However, the low intrinsic sensitivity of MRI to detect exogenous contrast agents and the lack of biodegradable microprobes have prevented its clinical development. Here, we synthetized a contrast agent for molecular MRI based on a previously unknown mechanism of self-assembly of catechol-coated magnetite nanocrystals into microsized matrix-based particles. The resulting biodegradable microprobes (M3P for microsized matrix-based magnetic particles) carry up to 40,000 times higher amounts of superparamagnetic material than classically used nanoparticles while preserving favorable biocompatibility and excellent water dispersibility. After conjugation to monoclonal antibodies, targeted M3P display high sensitivity and specificity to detect inflammation in vivo in the brain, kidneys, and intestinal mucosa. The high payload of superparamagnetic material, excellent toxicity profile, short circulation half-life, and widespread reactivity of the M3P particles provides a promising platform for clinical translation of immuno-MRI.

Method for the Identification of Potentially Bioactive Argon Binding Sites in Protein Families.

Argon belongs to the group of chemically inert noble gases, which display a remarkable spectrum of clinically useful biological properties. In an attempt to better understand noble gases, notably argon's mechanism of action, we mined a massive noble gas modeling database which lists all possible noble gas binding sites in the proteins from the Protein Data Bank. We developed a method of analysis to identify among all predicted noble gas binding sites the potentially relevant ones within protein families which are likely to be modulated by Ar. Our method consists in determining within structurally aligned proteins the conserved binding sites whose shape, localization, hydrophobicity, and binding energies are to be further examined. This method was applied to the analysis of two protein families where crystallographic noble gas binding sites have been experimentally determined. Our findings indicate that among the most conserved binding sites, either the most hydrophobic one and/or the site which has the best binding energy corresponds to the crystallographic noble gas binding sites with the best occupancies, therefore the best affinity for the gas. This method will allow us to predict relevant noble gas binding sites that have potential pharmacological interest and thus potential Ar targets that will be prioritized for further studies including in vitro validation.

Anticancer Drugs for Intra-Arterial Treatment of Colorectal Cancer Liver Metastases: In-Vitro Screening after Short Exposure Time.

To treat colorectal liver metastases, intra-arterial chemotherapies may complete therapeutic arsenal. Drugs using intra-arterially are very heterogeneous. The aim of this study was to select the most efficient drug on a panel of colorectal cancer (CRC) cell lines (Caco-2, HCT 116, HT 29, SW 48, SW 480, SW 620) exposed for 30 min to 12 cytotoxic agents (doxorubicin, epirubicin, idarubicin, 5-FU, raltitrexed, gemcitabine, cisplatin, oxaliplatin, mitomycin C, irinotecan, streptozocin, paclitaxel) at different concentrations. The effect on cell viability was measured using the WST-1 cell viability assay. For each drug and cell line, the IC50 and IC90 were calculated, which respectively correspond to the drug concentration (mg/mL) required to obtain 50% and 90% of cell death. We also quantified the cytotoxic index (CyI90 = C Max/IC90) to compare drug efficacy. The main findings of this study are that idarubicin emerged as the most cytotoxic agent to most of the tested CRC cell lines (Caco-2, HT29, HCT116, SW620 and SW480). Gemcitabine seemed to be the most efficient chemotherapy for SW48. Interestingly, the most commonly used cytotoxic agents in the systemic and intra-arterial treatment of colorectal liver metastasis (CRLM) (oxaliplatin, 5-FU, irinotecan) showed very limited cytotoxicity to all the cell lines.

Role of inflammation in alcohol-related brain abnormalities: a translational study.

Brain abnormalities observed in alcohol use disorder are highly heterogeneous in nature and severity, possibly because chronic alcohol consumption also affects peripheral organs leading to comorbidities that can result in exacerbated brain alterations. Despite numerous studies focussing on the effects of alcohol on the brain or liver, few studies have simultaneously examined liver function and brain damage in alcohol use disorder, and even fewer investigated the relationship between them except in hepatic encephalopathy. And yet, liver dysfunction may be a risk factor for the development of alcohol-related neuropsychological deficits and brain damage well before the development of liver cirrhosis, and potentially through inflammatory responses. The use of animal models enables a better understanding of the pathophysiological mechanisms underlying liver-brain relationships in alcohol use disorder, and more particularly of the inflammatory response at the tissue, cerebral and hepatic levels. The objective of this translational study was to investigate, both in alcohol use disorder patients and in a validated animal model of alcohol use disorder, the links between peripheral inflammation, liver damage and brain alterations. To do this, we conducted an in vivo neuroimaging examination and biological measures to evaluate brain volumes, liver fibrosis and peripheral cytokines in alcohol use disorder patients. In selectively bred Sardinian alcohol-preferring rats, we carried out ex vivo neuroimaging examination and immunohistochemistry to evaluate brain and liver inflammatory responses after chronic (50 consecutive weeks) alcohol drinking. In recently abstinent and non-cirrhotic alcohol use disorder patients, the score of liver fibrosis positively correlated with subcortical regions volumes (especially in right and left putamen) and level of circulating proinflammatory cytokines. In Sardinian alcohol-preferring rats, we found macrostructural brain damage and microstructural white matter abnormalities similar to those found in alcohol use disorder patients. In addition, in agreement with the results of peripheral inflammation observed in the patients, we revealed, in Sardinian alcohol-preferring rats, inflammatory responses in the brain and liver were caused by chronic alcohol consumption. Since the liver is the main source of cytokines in the human body, these results suggest a relationship between liver dysfunction and brain damage in alcohol use disorder patients, even in the absence of major liver disease. These findings encourage considering new therapeutic strategies aiming at treating peripheral organs to limit alcohol-related brain damage.

Rate of Rebleed and Retreatment of Previously Treated Intracranial Aneurysms.

BACKGROUND: Intracranial aneurysms (IAs) can be treated through endovascular treatment (EVT) or microsurgery (MS). Treated IAs can recanalize, which can lead to rupture or retreatment. OBJECTIVE: The aim of our study was to evaluate the natural history of previously treated IA, by evaluating the risk of rupture and the risk of retreatment. METHODS: All patients treated for an IA between 2007 and 2017 in 4 hospitals were included. The rate of (recurrent) hemorrhage and the rate of prophylactic retreatment were retrospectively evaluated. Kaplan-Meier survival analysis with log-rank tests was used to compare the rates of rupture or retreatment. Patients with ruptured and unruptured aneurysms were separated, and we compared the risk of retreatment between EVT and the surgical treatment. RESULTS: A total of 4997 IAs were included in the study, corresponding to 20,489 patient-years. Overall, 28 (0.6%) aneurysms that had been previously treated demonstrated hemorrhage. Moreover, 237 (4.7%) aneurysms were retreated for recanalization without hemorrhage. The rate of retreatment was higher in the EVT-treated IAs as compared with the MS-treated IAs (LogRank: P < 0.0001) and higher in the previously ruptured IAs versus unruptured IAs (LogRank: P < 0.0001). However, the rate of posttreatment hemorrhage/IA rupture was similar for both groups. CONCLUSIONS: The rate of IA retreatment is low; however, the rate of hemorrhage/rupture from treated IAs is even lower. A higher rate of retreatment was noted in EVT-treated IAs versus MS-treated IAs and in ruptured IAs versus unruptured IAs; however, the rate of hemorrhage or rerupture was comparable between the groups.

Autoimmune encephalitis mediated by B-cell response against N-methyl-d-aspartate receptor.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease characterized by an antibody-mediated autoimmune response against NMDAR. Recent studies have shown that anti-NMDAR antibodies are involved in the pathophysiology of the disease. However, the upstream immune and inflammatory processes responsible for this pathogenic response are still poorly understood. Here, we immunized mice against the region of NMDA receptor containing the N368/G369 amino acids, previously implicated in a pathogenic response. This paradigm induced encephalopathy characterized by blood-brain barrier opening, periventricular T2-MRI hyperintensities and IgG deposits into the brain parenchyma. Two weeks after immunization, mice developed clinical symptoms reminiscent of encephalitis: anxiety- and depressive-like behaviours, spatial memory impairment (without motor disorders) and increased sensitivity to seizures. This response occurred independently of overt T-cell recruitment. However, it was associated with B220+ (B cell) infiltration towards the ventricles, where they differentiated into CD138+ cells (plasmocytes). Interestingly, these B cells originated from peripheral lymphoid organs (spleen and cervical lymphoid nodes). Finally, blocking the B-cell response using a depleting cocktail of antibodies reduced the severity of symptoms in encephalitis mice. This study demonstrates that the B-cell response can lead to an autoimmune reaction against NMDAR that drives encephalitis-like behavioural impairments. It also provides a relevant platform for dissecting encephalitogenic mechanisms in an animal model, and enables the testing of therapeutic strategies targeting the immune system in anti-NMDAR encephalitis.

Alcohol exposure-induced neurovascular inflammatory priming impacts ischemic stroke and is linked with brain perivascular macrophages.

Alcohol abuse is a major public health problem worldwide, causing a wide range of preventable morbidity and mortality. In this translational study, we show that heavy drinking (HD) (≥6 standard drinks/day) is independently associated with a worse outcome for ischemic stroke patients. To study the underlying mechanisms of this deleterious effect of HD, we performed an extensive analysis of the brain inflammatory responses of mice chronically exposed or not to 10% alcohol before and after ischemic stroke. Inflammatory responses were analyzed at the parenchymal, perivascular, and vascular levels by using transcriptomic, immunohistochemical, in vivo 2-photon microscopy and molecular MRI analyses. Alcohol-exposed mice show, in the absence of any other insult, a neurovascular inflammatory priming (i.e., an abnormal inflammatory status including an increase in brain perivascular macrophages [PVM]) associated with exacerbated inflammatory responses after a secondary insult (ischemic stroke or LPS challenge). Similar to our clinical data, alcohol-exposed mice showed larger ischemic lesions. We show here that PVM are key players on this aggravating effect of alcohol, since their specific depletion blocks the alcohol-induced aggravation of ischemic lesions. This study opens potentially new therapeutic avenues aiming at blocking alcohol-induced exacerbation of the neurovascular inflammatory responses triggered after ischemic stroke.

Optimized tPA: A non-neurotoxic fibrinolytic agent for the drainage of intracerebral hemorrhages.

Intracerebral hemorrhage (ICH) is the most severe form of stroke. Catheter-delivered thrombolysis with recombinant tissue-type plasminogen activator (rtPA) for the drainage of ICH is currently under evaluation in a phase III clinical trial (MISTIE III). However, in a pig model of ICH, in situ fibrinolysis with rtPA was reported to increase peri-lesional edema by promoting N-methyl-D-aspartate (NMDA)-dependent excitotoxicity. In the present study, we engineered a non-neurotoxic tPA variant, OptPA, and investigated its safety and efficacy for in situ fibrinolysis in a rat model of ICH. Magnetic resonance imaging analyses of hematoma and edema volumes, behavioral tasks and histological analyses were performed to measure the effects of treatments. In vitro, OptPA was equally fibrinolytic as rtPA without promoting NMDA-dependent neurotoxicity. In vivo, in situ fibrinolysis using OptPA reduced hematoma volume, like rtPA, but it also reduced the evolution of peri-hematomal neuronal death and subsequent edema progression. Overall, this preclinical study demonstrates beneficial effects of OptPA compared to rtPA for the drainage of ICH.

ADAMTS-4 in oligodendrocytes contributes to myelination with an impact on motor function.

Myelination is a late developmental process regulated by a set of inhibitory and stimulatory factors, including extracellular matrix components. Accordingly, chondroitin sulfate proteoglycans (CSPGs) act as negative regulators of myelination processes. A disintegrin and metalloproteinase with thrombospondin motifs type 4 (ADAMTS-4) is an extracellular protease capable of degrading CSPGs. Although exogenous ADAMTS-4 has been proven to be beneficial in several models of central nervous system (CNS) injuries, the physiological functions of endogenous ADAMTS-4 remain poorly understood. We first used Adamts4/LacZ reporter mice to reveal that ADAMTS-4 is strongly expressed in the CNS, especially in the white matter, with a cellular profile restricted to mature oligodendrocytes. Interestingly, we evidenced an abnormal myelination in Adamts4-/- mice, characterized by a higher diameter of myelinated axons with a shifting g-ratio. Accordingly, lack of ADAMTS-4 is accompanied by motor deficits and disturbed nervous electrical activity. In conclusion, we demonstrate that ADAMTS-4 is a new marker of mature oligodendrocytes contributing to the myelination processes and thus to the control of motor capacities.

Network modeling of resting state connectivity points towards the bottom up theories of schizophrenia.

The dysconnectivity theory of schizophrenia proposes that schizophrenia symptoms arise from abnormalities in neuronal synchrony. Resting-state Functional Connectivity (FC) techniques allow us to highlight synchronization of large-scale networks, the Resting-state Networks (RNs). A large body of work suggests that disruption of RN synchronization could give rise to specific schizophrenia symptoms. The present study aimed to explore within- and between-network FC strength of 34 RNs in 29 patients suffering from schizophrenia, and their relationships with schizophrenia symptoms. Resting-state data were analyzed using independent component analysis and dual-regression techniques. Our results showed that both within-RN and between-RN FC were disrupted in patients with schizophrenia, with a global trend toward weaker FC. This decrease affected more particularly visual, auditory and crossmodal binding networks. These alterations were correlated with negative symptoms, positive symptoms and hallucinations, indicating abnormalities in visual processing and crossmodal binding in schizophrenia. Moreover, we stressed an anomalous synchronization between a visual network and a network thought to be engaged in mental imaging processes, correlated with delusions and hallucinations. Altogether, our results supported the assumption that some schizophrenia symptoms may be related to low-order sensory alterations impacting higher-order cognitive processes, i.e. the "bottom-up" hypothesis of schizophrenia symptoms.

Automatic Generation of Connectivity for Large-Scale Neuronal Network Models through Structural Plasticity.

With the emergence of new high performance computation technology in the last decade, the simulation of large scale neural networks which are able to reproduce the behavior and structure of the brain has finally become an achievable target of neuroscience. Due to the number of synaptic connections between neurons and the complexity of biological networks, most contemporary models have manually defined or static connectivity. However, it is expected that modeling the dynamic generation and deletion of the links among neurons, locally and between different regions of the brain, is crucial to unravel important mechanisms associated with learning, memory and healing. Moreover, for many neural circuits that could potentially be modeled, activity data is more readily and reliably available than connectivity data. Thus, a framework that enables networks to wire themselves on the basis of specified activity targets can be of great value in specifying network models where connectivity data is incomplete or has large error margins. To address these issues, in the present work we present an implementation of a model of structural plasticity in the neural network simulator NEST. In this model, synapses consist of two parts, a pre- and a post-synaptic element. Synapses are created and deleted during the execution of the simulation following local homeostatic rules until a mean level of electrical activity is reached in the network. We assess the scalability of the implementation in order to evaluate its potential usage in the self generation of connectivity of large scale networks. We show and discuss the results of simulations on simple two population networks and more complex models of the cortical microcircuit involving 8 populations and 4 layers using the new framework.