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Section: Partnerships and Cooperations
National Initiatives
ANR
ANR-NIH-NSF NETBCI
Participants : Fabrizio de Vico Fallani [Correspondant] , Mario Chavez, Denis Schwartz.
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Project title: Modeling and predicting brain-computer interface learning from dynamic networks
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Abstract: This project will bring together expertise in computational and experimental neuroscience, signal processing and network science, statistics, modeling and simulation, to establish innovative methods to model and analyze temporally dynamic brain networks, and to apply these tools to develop predictive models of brain-computer interface (BCI) skill acquisition that can be used to improve performance. Leveraging experimental data and interdisciplinary theoretical techniques, this project will characterize brain networks at multiple temporal and spatial scales, and will develop models to predict the ability to control the BCI as well as methods to engineer BCI frameworks for adapting to neural plasticity. This project will enable a comprehensive understanding of the neural mechanisms of BCI learning, and will foster the design of viable BCI frameworks that improve usability and performance.
ANR-NIH-NSF HIPLAY7
Participants : Olivier Colliot [Correspondant] , Marie Chupin, Stanley Durrleman, Anne Bertrand.
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Project title: Hippocampal layers: advanced computational anatomy using very high resolution MRI at 7 Tesla in humans
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Coordinator: Olivier Colliot and Pierre-François Van de Moortele
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Abstract: The overall goal of this proposal is to develop a coherent mathematical framework for computational anatomy of the internal structures of the hippocampus based on cutting edge MRI acquisition techniques at 7 Tesla. These mathematical and computational approaches are expected to significantly advance the field of computational anatomy of the human brain, breaking down the millimeter barrier of conventional brain morphometry and providing a coherent analysis framework for anatomical data at ultra-high spatial resolution.
ANR PREV-DEMALS
Participants : Olivier Colliot [Correspondant] , Marie Chupin, Stanley Durrleman, Anne Bertrand.
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Project title: Predict to prevent frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)
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Other partners: ICM, AP-HP, CHR de Lille, CHU Limoges, CHU Rouen, Laboratory of Biomedical Imaging
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Abstract: The project focuses on C9ORF72, the most frequent genetic form of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Since 2006, major discoveries have helped elucidate the pathological bases and linked FTLD and ALS: 1) TDP-43 aggregates in neurons and 2) C9ORF72 mutations in both disorders. Two major pathological subtypes are now defined in FTLD, FTLD-TDP and FTLD-TAU. C9ORF72 mutations (associated to FTLD-TDP) are the most frequent genetic causes of FTLD (15%), FTLD-ALS (65%) and ALS (40%). No curative treatment actually exists, but therapeutics emerged against tau aggregation. The objectives of the project are to develop appropriate cognitive, brain imaging markers and peripheral biomarkers of the early phase of FTLD, to follow disease progression and to guide future targeted therapeutic trials. To address this questions, we will conduct a multimodal study (cognition, brain structural MRI, brain metabolism - FDG-PET) in C9ORF72 families. The cohort will be followed at 3-time points (M0, M18, M36). Longitudinal analyses will aim at characterizing the trajectory of decline across time. Brain structural changes will be evaluated by 1) morphometric analysis to assess global brain atrophy, cortical thickness and study of the cortical sulci; 2) functional connectivity analysis of resting-state MR data; 3) structural connectivity analysis of diffusion-weighted MRI. Brain metabolism will be evaluated with FDG-PET. We will use the most recent RNA sequencing technology to detect gene expression and RNA splicing alterations in lymphocytes of patients and presymptomatic carriers. The discovery of new markers involved in FTLD will have practical consequences for early and accurate diagnosis of FLD and ALS disease.
ANR IVMRS
Participants : Anne Bertrand [Correspondant] , Alexandra Petiet, Mathieu Santin, Francesca Branzoli, Benoit Delatour, Marc Sanson.
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Project title: Implantable miniaturized probe for In-vivo Magnetic Resonance Spectroscopy: Application to Murine models of Alzheimer’s disease and Gliomas.
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Other partners: ICube - Unistra, Strasbourg; ISA Laboratory, Lyon; NYU School of Medicine, NY, USA.
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Abstract: During the development of new therapeutics against brain diseases, the pre-clinical phase, i.e. the validation of treatment delivery, safety and efficacy in animal models of the disease, represents a crucial step. Magnetic Resonance Imaging (MRI) is a method of particular interest at this stage, as it provides non-invasive surrogate endpoints that can help selecting appropriate candidates during the process of drug development. Single Voxel Magnetic Resonance Spectroscopy (SVS) provides non-invasive, in-vivo quantitative measurements of brain metabolites, which reflects functional changes at the cellular and subcellular levels, and can be repeated longitudinally. As high-field MRI has become the benchmark in preclinical research on animal models, it appears possible to investigate the cerebral metabolomics changes in animals, and to use it as a surrogate marker in preclinical therapeutic trials. However, the number of relevant metabolites is much higher than the low number of measurable metabolites with conventional in-vivo high-field SVS. Moreover, considering also the subtle changes of these metabolites at the early stage of the disease, the use of conventional high-field SVS in preclinical studies remains strongly limited. The high volume of the Voxel-of-Interest (VOI), ranging from 10 to 30mm3, which is required to have a usable signal in conventional SVS, and the inherent variability of longitudinal SVS measurement due to the variable position of the VOI in the successive experiments, remain the two major issues when looking during time for small changes in metabolic concentrations and metabolites ratios in a specific small region of the animal brain. The IvMRS project aims at filling this gap by developing the first chronic implantable MRS micro-probe, minimally invasive, exhibiting very high signal sensitivity, and sharp spectral peaks, from sub-millimetric VOI. Such a probe will allow detecting a much higher number of metabolites than conventional in-vivo SVS. The probe will work at frequencies ranging from 300MHz to 500MHz in ultra-high field Magnetic Resonance Imaging scanners, 7T and 11.7T. It will embed a specific micro-coil antenna, a low-noise signal conditioning circuit designed in CMOS microelectronics technology, as well as an accurate on-chip positioning sensor. It will be dedicated to the study of changes in brain metabolite markers of two major diseases, Alzheimer's disease and cerebral gliomas, and to the assessment of effective therapeutic strategies.
Inria Project Labs
IPL Neuromarkers
Participants : Stanley Durrleman [Correspondant] , Olivier Colliot [Correspondant] , Fabrizio de Vico Fallani, Anne Bertrand, Stéphane Epelbaum.
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Project title: Design of imaging biomarkers of neurodegenerative diseases for clinical trials and study of their genetic associations
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Other partners: Inria GENSCALE, Inria BONSAI, Inria DYLISS, Inria XPOP, ICM, IHU/ICM iConics
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Abstract: The Inria Project Lab Neuromarkers aims to develop new statistical and computational approaches to integrate multimodal imaging and omics data and to demonstrate their potential to identify early alterations and predict progression of neurodegenerative diseases. To tackle this challenge, the project brings together multidisciplinary expertise from Inria and ICM (Brain and Spine Institute) in the fields of statistical learning, brain imaging, bioinformatics, knowledge modeling, genomics and neurodegenerative diseases.
IHU
General program
Participants : Olivier Colliot, Stanley Durrleman, Didier Dormont, Ninon Burgos, Stéphane Epelbaum, Fabrizio de Vico Fallani.
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The IHU-A-ICM program was selected, in 2011, in a highly competitive national call for projects. A 10-year, 55M€ program, has been implemented by a recently created foundation for scientific cooperation. Based on the clinical and scientific strenghts of the ICM and the hospital Department of Nervous System Diseases, it mainly supports neuroscience research, but is also invested in improving care and teaching. ARAMIS is strongly involved in the IHU-A-ICM project, in particular in WP6 (neuroimaging and electrophysiology), WP7 (biostatistics), WP2 (Alzheimer) and WP5 (epilepsy). We have started collaborations with the new bioinformatics/biostatistics platform (IHU WP7, head: Ivan Moszer), in particular through a joint project on the integration of imaging and genomics data.
ICM-Internal Research projects
Participants : Anne Bertrand [Correspondant] , Takoua Kaaouana, Benoit Delatour, Alexandra Petiet, Olivier Colliot, Arnaud Marcoux.
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Project title: The Histo-MRI project: targeting MR signature of tauopathy from micro- to macroscopy
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Identifying morphological MR signatures of brain diseases usually follows a top-down process, which starts by describing a pattern of MR signal changes in patients, hypothesizes an underlying pathological mechanism, and confirms this mechanism by correlating the observed MR signal changes with histological lesions on post-mortem examination. This top-down process, relevant for large, centimetric brain lesions, becomes inappropriate when targeting the MR signal intensity changes associated with microscopic lesions. Our project aims at developing an MR biomarker of NFT using a new bottom-up approach. We will start by identifying the MR signal changes associated with the presence of NFT at the level of the histological slice, and utilize these findings to develop a method of NFT quantification on clinical, millimetric 3D MR images. To achieve this goal, we will develop and implement a 11.7T histological coil dedicated to the scanning of histological slices, which allows both ultra-high resolution MR imaging (up to 33 microns in-plane) and perfect co-registration with histological staining, performed subsequently on the same slice. This method has the potential to provide a novel biomarker of tauopathy that could not have been identified using the usual top-down approach. It also envisions the possibility to describe and understand new MRI contrasts in other neurodegenerative diseases associated with microscopic deposition of various proteins.
ICM-Internal Research projects
Participants : Mario Chavez, Fabrizio de Vico Fallani [Correspondant] .
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Project title: Non-invasive manipulation of brain synchrony to enhance brain function and rehabilitate faulty cognition in humans: A proof of concept
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Coordinator: Antoni Valero Cabre (ICM-team “Dynamiques Cérébrales, Plasticité et Rééducation”)
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Other partners: Service des Urgences Cérébro-Vasculaires de l'Hôpital Pitié-Salpêtrière, Paris.
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The long-term goal of this project is to develop the use of non-invasive manipulation of abnormal cerebral oscillations underlying cognitive activity to restore brain function in neurological patients. Cognitive functions emerge from large distributed networks organized in space and time. The short-term goal of this application is to study the causal role played by oscillatory activity in visual awareness and test whether their manipulation by non-invasive brain stimulation has the potential to restore its function in stroke patients.
ICM BBT Program - project PredictICD
Participants : Olivier Colliot [Correspondant] , Jean-Christophe Corvol [Correspondant] , Johann Faouzi.
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Project title: Predict impulse control disorders in Parkinson’s disease (PREDICT-ICD)
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Coordinators: Olivier Colliot and Jean-Christophe Corvol (ICM)
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In Parkinson’s disease (PD), the therapeutic strategy is based on the dopamine replacement therapy. Although available since the 1960s’, it is only relatively recently that behavioral disorders associated with these drugs have been described. Gathered under the term of “behavioral addiction”, they include impulse control disorders (ICDs), dopamine dysregulation syndrome (DDS), and punding. Interestingly, whereas addiction to L-dopa itself occurs quasi exclusively with L-dopa, ICDs appear electively under dopamine agonist (DA) therapy. The objectives of this project are: i) to elucidate the genetic basis of DA induced ICDs in PD patients from several international cohorts; ii) to develop and validate a machine learning model to predict the occurrence of ICDs from the combination of clinical and genetic data.
ICM BBT Program - project DYNAMO
Participants : Stanley Durrleman [Correspondant] , Harald Hampel [Correspondant] , Sabrina Fontanella, Simone Lista, Olivier Colliot, Stephanie Allassonniere, Jean-Baptiste Schiratti, Bruno Dubois, Hovagim Bakardjian, Remi Genthon, Enrica Cavedo, Katrine Rojkowa.
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Project title: Dynamic models of disease progression across Alzheimer’s disease stages informed by multimodal neuroimaging and biological data
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Other partners: Institut de la Mémoire et de la maladie d'Alzheimer
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The estimation of data-driven models of disease progression for neurodegenerative diseases, including Alzheimer’s disease (AD), is crucial to confirm, refine and extend the current hypothetical models. The estimation of such quantitative models from longitudinal data sets is notably difficult because of the lack of principled methodological frameworks for the analysis of spatiotemporal data.
The project builds on an innovative mathematical, statistical, and computational framework to automatically align the dynamics and the direction of individual trajectories of the evolving pathology, and then to infer a normative scenario of disease progression across different disease stages. The estimated scenario will combine spatiotemporal maps of lesion propagation, such as maps of amyloid deposition or cortical atrophy, and global measurements such as levels of CSF biomarkers. It will be possible to estimate not only a normative scenario but also the inter-individual variability in the values, dynamics and direction of both topographical and pathophysiological biomarkers changes during the course of the disease.
The application of this technology to publicly available and in-house longitudinal data sets of individuals from the asymptomatic at risk to the prodromal and dementia stages will yield new insights into the pathophysiology of AD from the preclinical to the AD dementia stages. This quantitative data-driven approach will be exploited to assess and refine the current qualitative hypothetical models of AD progression. Notably, it will complement these models with typical pathways of lesion propagation in the brain during disease progression. It will also highlight the effect of the known risk factors of AD such as apolipoprotein E genotype on the disease progression profile.
The project will open up the concrete possibility to derive a computer-aided diagnosis, staging, and prognosis tool for a better recruitment of patients in clinical studies and to assist clinicians in the diagnosis and the monitoring of both disease progression and treatment efficacy.
ICM BBT Program - project SEMAPHORE
Participants : Stanley Durrleman [Correspondant] , Stéphane Lehéricy [Correspondant] , Jean-Christophe Corvol, Marie Vidailhet, Raphael Couronné, Safia Said.
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Project title: Personalized progression model of Parkinson’s disease
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Other partners: Neurology and Neuro-radiology departments, Pitié-Salpêtrière Hospital, AP-HP
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The aim of this project is to build a personalizable model of Parkinson’s disease (PD) progression integrating the complex dynamical interplay between phenotypic, imaging, genetic and metabolic alterations. We will identify and validate markers for monitoring of progression of brain damage in early and prodromal PD and identify conversion markers in subjects at risk of PD (idiopathic rapid eye movement sleep behavior disorders iRBD, PD- related mutation carriers). We will describe the appearance, characterize clinical phenotypes of PD, and identify modifier genes of disease phenotype. To this aim, we will relie on a novel statistical learning method using Bayesian non-linear mixed-effects model allowing to combine and realign short term sequence data to estimate a long-term scenario of disease progression. This method is able to estimate individual stages of disease progression and to analyze automatically non-linear spatiotemporal patterns of data change. It estimates both a group-average scenario of PD progression as well as the inter-individual variability of this model in terms of age at onset, pace of disease progression and variability in the spatiotemporal trajectory of data changes. We will analyse the effect of genetic variants in the modulation of these non-linear progression patterns, and assess the statistical power of the individual parameters encoding for these patterns. The method will be applied to two sets of longitudinal data from the local prospective NUCLEIPARK (60 PD patients, 20 patients with iRBD, 60 controls) and ICEBERG studies (200 early idiopathic PD, 50 iRBD, 30 GBA and LRRK2 PD-related mutation carriers, 50 controls). Examinations included clinical, biological, and neurophysiological data, and multimodal 3T MRI, DATScan, and skin and salivary gland biopsies. The models of PD progression for each category of subjects will be released to the community, as well as the software for reproducibility purposes.
ICM BBT Program - project ATTACK
Participants : Fabrizio de Vico Fallani [Correspondant] , Charlotte Rosso [Correspondant] , Marie-Constance Corsi, Laurent Hugueville.
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Project title: ATTACK Brain Network Models Of Motor Recovery After Stroke
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Other partners: Neurology and Stroke departments, Pitié-Salpêtrière Hospital, AP-HP
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Like in other connected systems, studying the structure of the interactions between different brain regions has profound implications in the comprehension of emergent complex phenomena as, for example, the capability of the human brain to functionally reorganize after cerebrovascular "attacks" or stroke. This dynamic skill, which is known in neuroscience as neural plasticity, is not only interesting from a network science perspective, but it also plays a crucial role in determining the motor/cognitive recovery of patients who survive a stroke. As a critical innovation, this project proposes to develop a systematic and rigorous approach based on neuroimaging techniques, signal processing, and network science for the modeling and analysis of temporally dynamic neural processes that characterize motor recovery after stroke. To achieve these goals, this project is organized around the following objectives: i) acquiring a comprehensive longitudinal dataset of brain and behavioral/clinical data after stroke, ii) developing new analytic tools to characterize and generate temporally dynamic brain networks, iii) building network-based models of motor recovery after stroke, accounting for individual patients. These objectives involve an intensive gathering of heterogeneous mass data, their processing, the subsequent outcome interpretation and statistical simulation, as well as the development of longitudinal models and network-based diagnostics of the patient's motor recovery progress. Results will be first characterized from pure network-theoretic and neuroscience perspectives, so as to highlight fundamental research challenges, and then validated to clarify the importance and the applicability to the clinical scenario. Our results will unveil multiscale properties of dynamic brain networks and identify predictive neuromarkers for motor recovery after stroke. This project has a two-fold impact on the society. On the one hand, it will provide new methods and robust tools to properly characterize and model temporally dynamic networks in neuroscience. On the other hand, it will provide longitudinal models of motor recovery in stroke patients that can potentially unveil the neural substrate that underpins rehabilitation, improve prognosis, and eventually lower cost of hospitalization time. From a broader perspective this interdisciplinary project proposes a transformative approach to analyze large-scale neural systems.
National Networks
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GdR Statistics and Medicine - http://gdr-stat-sante.math.cnrs.fr/spip/
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GdR (MaDICS) Masses de Données, Informations et Connaissances en Sciences Big Data - Data ScienceStatistics and Medicine - http://www.madics.fr/reseaux/
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F. De Vico Fallani participated to the GdR (HANDICAP) in the framework of the future strategy of Inria
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F. De Vico Fallani was founding member of the CORTICO national network for brain-computer interfaces
Other National Programs
Programme Hospitalier de Recherche Clinique (PHRC)
Participants : Olivier Colliot, Stanley Durrleman, Didier Dormont.
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PHRC PredictPGRN, co-funding by Alzheimer Plan, Caractérisation multimodale prospective de la démence frontotemporale dûe à des mutations du gène PGRN à un stade symptomatique et présymptomatique. (Coordinator : A. Brice)
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PHRC ImaBio3, co-funding by Roche (pharmaceutical industry), Rôle des réactions cellulaires sanguines, inflammatoires et immunitaires anti-amyloïde centrales et périphériques dans la maladie d’Alzheimer débutante. (Coordinator : M. Sarazin)
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PHRC CAPP, Caractérisation linguistique, anatomique/métabolique et biologique des différentes formes d'aphasie primaire progressive : vers le rationnel pour des essais pharmacologiques et des rééducations du langage ciblées. (Coordinator: M. Teichmann)
Institut Universitaire d’Ingénierie pour la Santé (IUIS)
Participants : Mario Chavez, Xavier Navarro.
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Project title: Dépistage de la dyspnée par potentiels évoqués visuels
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Abstract: Steady state visual evoked potentials (SSVEP) have been widely utilized in brain computer interfacing (BCI) in last years. In this project, we explore the possibilities of SSVEP to manage the communication between patients suffering from respiratory disorders and health care providers. By imposing different breathing constraints, we use a SSVEP-based brain computer interface to help those subjects to communicate their breathing sensations (breathing well/breathing bad).