INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE Brain & Spine Institute - PARIS

INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE Brain & Spine institute - PARIS

SEARCH, FIND, CURE, FOR YOU & WITH YOU P 4 - EDITORIALS P 7 - ORGANIZATION OF RESEARCH AT THE ICM

P 15 - 2014 in Review

P 17 - RESEARCH

P 59 - THE IHU-A-ICM

P 69 - TECHNICAL PLATFORMS

P 97 - THE CLINICAL INVESTIGATION CENTER

P 105 - RESEARCH APPLICATIONS

TABLE OF CONTENTS OF TABLE P 109 - KEY FIGURES

P 117 - LIFE AT THE ICM

P 125 - GOVERNANCE, OVERSIGHT, AND TRANSPARENCY IntroductoryPrésentation remarks des équipes by the Presidentde l’Institut and Director-General of the ICM

Presentation of the teams of the institute

1 - Neurodegenerative diseases 2 - Multiple sclerosis 1 3 - Brain tumors 4 - Epilepsies 5 - Cognition, behavior, and psychiatric diseases 6 - Modeling 7 - Rare diseases 8 - Basic mechanisms underlying the development and function of the nervous system Glossary

1 - Major achievements 2 - Major publications 2 1 - Molecular exploration 2 - Cellular exploration 3 - Cellular imaging 3 4 - Functional exploration 5 - Preclinical functional exploration- phenoparc 6 - Bioinformatics and biostatistics – iconics 7 - Biological Resource Center

1 - Parkinson’s Disease 2 - Neurogenetics 4 3 - Alzheimer’s Diseases 4 - Multiple sclerosis 5 - Amyotrophic lateral sclerosis 6 - Rare diseases 7 - Understand brain function: motivation 8 - Participatory medicine

1 - Transform knowledge and promote research 2 - iPEPS-ICM companies 5 1 - Fundraising 2 - Use of Resources Statement 6 3 - Balance sheet 1 -Scientific and extra-scientific events 7 2 -Publicity campaigns 1 -Governance and oversight: Board of Administration, Founding Members, Scientific Council,Comité de la charte 8 2 -Friends of the ICM Circle EDITORIAL

Hope. It’s the key word for 2014, thanks to the This year, the first international companies arrived at enthusiasm and achievements of our researchers and the ICM: Neoventure Technologies (Ontario), which our partners, growing in numbers by our side. develops new biomarkers for Alzheimer’s disease and PathMaker (Boston), which is developing a method for The year 2013 was encouraging, and 2014 has been electrical stimulation of the spinal cord. rich in discoveries and progress thanks to all those who take part in the daily life of the ICM. To progress it is The iPEPS-ICM obtained seven new patents, and three necessary to take risks and try approaches that might projects developed at the iPEPS-ICM won worldwide lead to breakthroughs at the interface between different innovation competitions: DREEM, Brain-e-NOVATION, scientific fields. In order to advance it is necessary to which is creating e-health solutions, and Bio serenity, develop new unconventional approaches and new which is developing an “intelligent health” solution for methodologies. This is what we have done every day tracking and diagnosing epilepsy. since the inauguration of the ICM in September 2010. Several events also marked the year 2014. A new Many of these discoveries and projects allowed us to publicity campaign was launched, and new supporters progress in our understanding of the diseases of the have joined in this formidable human and scientific brain and spinal cord: adventure.

• The discovery of a peptide of viral origin gives Finally, I wish to acknowledge the loyalty of our partners, new hope for patients with Parkinson’s and other sponsors, companies, and regular donors, large and neurodegenerative diseases. The research, conducted small, who contribute every day to build the medicine on mice, demonstrated the existence of a peptide that of tomorrow. can protect against degeneration of neurons implicated in Parkinson’s disease. This discovery gives hope for for The year 2015 will be very important for the institute, th the future of preventing neurodegenerative diseases. which will celebrate its 5 anniversary since opening. 2015 will also be the moment for a first evaluation, • The INSIGHT study was launched in collaboration which we owe to all those who accompanied the with the Institute of Memory and Alzheimer’s Disease development of this center of reference for diseases of (I2MA) and the Pfizer research laboratory in the IHU-A- the nervous system. We will be mobilized so that this ICM. The aim of this five to six year study is to observe year will also be synonymous with new discoveries and and understand the evolution of Alzheimer’s Disease rich in challenges. My thanks to all of you who made in a cohort of at-risk people in order to identify the the adventure of the ICM possible and who have stood factors that initiate the disease. 400 healthy subjects alongside us to overcome the diseases of the brain and will be selected to participate in the study. All of these spinal cord. players are motivated to better understand and hope to ultimately treat the disease

Since 2012, the ICM has published more than 1000 scientific articles, with a significant increase in impact factor over time. Additionally, five researchers were honored with prizes: Claire Wyart for the Irene Joliot- Curie prize, Mohammed El Behi for the Foundation Bouvet-Labruyère prize, Luc Mallet for the Marcel Dassault prize, Mathias Pessiglione and Lionel Naccache for the prize of the Academy of Science. All of this attests to the excellence of the 600 researchers, engineers, and technicians at the institute.

With six new companies joining in 2014, the business incubator iPEPS-ICM now hosts 20 companies in Professor partnership with the institute. Gérard Saillant President of the ICM EDITORIAL

The ICM is on the right track. Already recognized as amajor The ICM is now recognized internationally in the contributor to research on the nervous system and its neuroscience community. This has led to the establishment pathologies, both on the national and international scale, of strategic alliances with the Institute of Neurology (UCL, the major achievements of 2014 illustrate the medical London, UK) and the DZNE (Helmholtz, Germany), with and scientific advances made in a number of domains which the ICM participates in joint European projects. and bear witness to the creativity and engagement of our Exchanges are developing with the Sandler Institute (USCF, researchers and personnel. San Francisco, USA), Yale University (New Haven, USA), and the Florey Institute (Melbourne, Australia), primarily Our new ICM research unit, created on January 1, 2014 among students. A joint workshop was held this year in with our institutional partners, CNRS, INSERM, Pierre Montreal with the Montreal Neurological Institute and and Marie Curie University, is composed of 25 teams Hospital (McGill, Montreal, Canada). Fundraising has also that have been renewed. These teams cover numerous become international, the first international fundraising domains, both fundamental and translational. In order to event took place in London in April 2014. reinforce and vitalize the institute, the ICM and the IHU-A- ICM launched an international call for projects to recruit The quality of the scientific events of the institute is now one or more new teams. Almost a hundred applicants established. Prestigious lectures by eminent international submitted projects and several members of our Scientific figures are complemented by monthly lectures on the Advisory Board came to the ICM to interview a dozen that arts, culture, and science that bring together donors were preselected on the basis of their scientific excellence. and the personnel of the ICM. The institute is an unique Following this procedure, the team directed by Bassem place for training and is associated with Pierre and Marie Hassan was chosen and will join the institute in 2016. We Curie University. Furthermore, thanks to “les Ajités,” an have optimized and reconfigured different parts of the association of students and post-doctoral fellows that building in order to house all of the teams. The organization organizes numerous events, a new dynamic of discussions of the platforms has also evolved with the creation of a and scientific reflection for the youngest members of the Platform Committee for greater reactivity and better Institute has been ushered in. coordination and to anticipate the needs of the researchers Finally, interaction with the business world is accelerating by participating in the technological development of the thanks to the 20 start-ups incubated in the iPEPS-ICM Institute. The first day dedicated to institute platforms that collaborate with local teams, four of which originated allowed us to communicate the capability of these platforms in the ICM. In addition, we organized meetings with to researchers and enterprises, both within and outside the entrepreneurs, and the ICM hosted many events dedicated Institute. Additionally, new platforms were created, such as to innovation and technology transfer. In this context, PRISME for the study of behaviors in ecological situations the commercialization of the first licenses for patents or virtual reality, and other platforms were reinforced, generated in the ICM is an encouraging sign. such as with the development of optogenetics in vivo and the creation of a therapeutic evaluation center (CET) All the elements are thus in place to make the original associated with our Clinical Investigations Center (CIC). ecosystem of the ICM a terrain for very high level research that will not only advance the frontiers of knowledge but The first institute retreat was a moment of discussion and will also develop applications for the benefit of patients. conviviality during which all personnel could discover the multiple facets of the institute. The retreat was also the I wish to thank most sincerely all those who have had faith occasion to accelerate the ICM 2020 program, a strategic in us and have supported us including founding members, program involving all members of the institute. Another the Friends Circle of the ICM, donors, sponsors, institutional emphasis was scientific strategy and transversal projects partners, and others for their faith and their loyalty at our associating the technology and expertise of the teams and sides so that we can work together to succeed in expanding platforms in order to advance further at the interfaces the ambition of the ICM to new frontiers. between disciplines. Given the success of these interactions, it was decided to launch a call for joint projects by the ICM and the IHU-A-ICM to support the most innovative and original transversal projects in 2015. In parallel, work Professor groups have been created to make proposals as to how to better live and work together, increase the influence of Alexis Brice the institute, and develop a feeling of belonging. Concrete measures have already been taken thanks to the broad Director General of the ICM participation of the vital forces of the Institute.

ORGANIZ ATION OF RESEARCH IN THE ICM

ICM ANNUAL REPORT 2014 7 ORGANIZ ATION OF RESEARCH IN THE ICM

TEAM LEADERS PRINCIPAL INVESTIGATORS

AXIS: “NEURODEGENERATIVE DISEASES”

TEAM “CAUSES OF ALS AND THE MECHANISMS OF MOTOR NEURON DEGENERATION” Séverine Boillée Christian Lobsiger Delphine Bohl Stephanie Millecamps Danielle Seilhean Vincent Meininger François Salachas The team was supported by the: Agence Nationale de Recherche, Association pour l’étude de la culture d’embryon, Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autre maladies du motoneurone, Association France Parkinson, Aide à la recherche des Maladies du Cerveau, Institut Pasteur/Labex REVIVE consortium, Institut Pasteur/Association Française contre les Myopathies

TEAM: “MOLECULAR BASES, PHYSIOPATHOLOGY, AND TREATMENT OF NEURODEGENERATIVE DISEASES”

Alexis Brice Morwena Latouche Hartmann Alexandra Durr Annie Sittler Fanny Mochel Christel Depienne Isabelle Le Ber Olga Corti Suzanne Lesage Giovanni Stevanin Jean-Christophe Corvol Fredéric Darios Caroline Nava

The team was supported by the: Agence Nationale de la Recherche, APHP, École de Neurosciences Paris Ile de France, INSERM (Cossec), Université de Toulouse, Agence Nationale de Sécurité du Médicament et des Produits de Santé, European Commission,UCL University et Fondation High Q. USA, University Hospital of ULM, Association Française de l’Ataxie de Friedreich, Association Française contre les Myopathies, Association des personnes concernées par le tremblement essentiel, Association Strümpell-Lorrain, Association Connaître les Syndromes Cérébelleux, Fondation de France, Fondation Maladies Rares, Fondation Plan Alzheimer, Association France Alzheimer, Association France Parkinson, Association PSP France, Fondation pour la Recherche Médicale, Prix Académie des sciences, Elisabeth Badinter, Insituto de Biologia Molecular e Cellular, Prix Fondation Roger de Spoelberch Suisse,The Michael J Fox Foundation, Fondation Carlo Besta (contrat doctoral), Fondation Jacques et Gloria Gossweiler, VERUM Fondation, Baylor Research Institute BRI, CHDI Foundation, SERVIER, SANOFI-AVENTIS, IPSEN Innovation, Pfizer Pharmanet Suisse, Pfizer, ULTRAGENIX, UCB Pharma S.A. France, Fondation EDF

TEAM: “ALZHEIMER’S AND PRION DISEASES” Stéphane Haik Benoit Delatour Marie-Claude Potier Charles Duyckaerts Nicolas Bizat Stéphane Epelbaum The team was supported by the: Agence Nationale de Recherche, BPI France Ile de France Paris, Institut de Veille Sanitaire, Fondation Jérôme Lejeune, Fondation pour la Recherche Médicale, Ligue Européenne contre la Maladie Alzheimer (LECMA), ROCHE, Prix Fondation Claude Pompidou, Association Robert Debré, Elisabeth Badinter, anonymous donation, LFB Biomedicaments, SERVIER, OSEO

8 ICM ANNUAL REPORT 2014 TEAM LEADERS PRINCIPAL INVESTIGATORS

TEAM: “NEUROGENETICS AND PHYSIOLOGY” Bertrand Fontaine Cécile Delarasse Sophie Nicole Mohamed El Behi Bruno Eymard Isabelle Rebeix Laure Strochlic

The team was supported by the: Agence Nationale de Recherche, Assistance Publique-Hôpitaux de Paris, Association Française de l’Hémiplégie Alternante, Association contre les Myopathies, ARSEP - Aide à la Recherche sur la Sclérose en Plaques, Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres maladies du motoneurone, Fondation de France (Prix Bouvet- Labruyère-ICM 2013), Fondation Maladies Rares, OSEO (defi), BIOGEN, OCIRP, Pharnext

TEAM: “EXPERIMENTAL THERAPEUTICS FOR PARKINSON’S DISEASE” Etienne Hirsch Chantal Francois David Grabli Stéphane Hunot Rita Raisman Marielaure Welter Patrick Pierre Michel Annie Lannuzel The team was supported by the: Agence Nationale de la Recherche, INSERM (contrat d’interface), INSERM (ITMO), CHU Pointe à Pitre, ICM, European Commission, PSP France, Association pour la recherche sur les Nicotianées, Fondation RATP, Air Liquide, BOIRON, SERVIER, KLESIA, INTERNATIONAL ESSENTIAL TREMOR FOUNDATION

TEAM: “TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS: FROM GENETICS TO ZEBRAFISH” Edor Kabashi The team was supported by: Inserm Atip Avenir, European Commission, DOF (Department Of Defense), Université de Montréal via SLA, IHU-The Johns Hopkins University, Association France Alzheimer, Fédération pour la Recherche sur le Cerveau, Institut de Recherche sur la Moelle Epinière et l’Encéphale, Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres maladies du motoneurone, Fondation Cognac Jay, KLESIA

TEAM: “EXPERIMENTAL NEUROSURGERY” Brian Lau Carine Karachi The team was supported by: INSERM ATIP Avenir, Agence Nationale de Recherche, European Commission, Association France Parkinson, Institut de France, Simons Foundation, SANOFI-AVENTIS, Jean-Louis and Marie Cécile Dufloux

TEAM: “ABNORMAL MOVEMENTS AND THE BASAL GANGLIA: PHYSIOPATHOLOGY AND EXPERIMENTAL THERAPEUTICS” Stéphane Lehericy Isabelle Arnulf Marie Vidailhet Emmanuel Roze Pierre Pouget Sabine Meunier Sophie Rivaud Andréas Hartman

This team was supported by the: Agence Nationale de la Recherche, INSERM, INSERM (COSSEC), CNRS (Contrat d’interface), ICM, Association Française de l’Hémiplégie Alternante, Association Française du Syndrome de Gilles de La Tourette, Association des personnes concernées par le tremblement essentiel, Association France Parkinson, Fondation Bettencourt Schueller / Projet Ultrabrain, Fondation de l’avenir, Fondation Groupama, Fondation Maladies Rares, Fondation Pierre Gilles de Gennes pour la Recherche, Fédération pour la Recherche sur le Cerveau, Fondation pour la Recherche Médicale, 2ne contract (PI Sabine Meunier): January 1 2014-April 30 Avril 2015 (80 000€ en 2014), NEB (Naturalia et Biologia), Prix Fondation NRJ, Genzyme France, GSK Glaxosmithkline, IP SANT2, IPSEN Innovation, LILLY, Merz Pharma, Novartis Pharma, ROCHE, SERVIER, TEVA France, UCB Pharma France S.A, Fonds Patrick de Brou de Laurière, Fonds de dotation Pierre Bergé, Fondation AREVA / projet Gamma, Fondation EDF

ICM ANNUAL REPORT 2014 9 ORGANIZ ATION OF RESEARCH IN THE ICM

TEAM LEADERS PRINCIPAL INVESTIGATORS

AXIS: “NEURONAL EXCITABILITY, NERVE TRANSMISSION, AND DISEASES ASSOCIATED WITH EPILEPSY”

TEAM: “SYNAPTIC INHIBITION AND AUTO-MODULATION OF MICROCIRCUITS OF THE CEREBRAL CORTEX” Alberto Bacci The team was supported by the: Cette équipe a bénéficié du soutien de : Agence Nationale de Recherche, European Commission, Ministère de l’Egalité des Territoires et du Logement, Ecole des Neurosciences Paris Ile de France, Brain and Behavior Foundation (ex Narsad), Telethon Italia, ICM

TEAM: “DYNAMICS AND PHYSIOPATHOLOGY OF NEURONAL NETWORKS” Stéphane Charpier Mario Chavez Séverine Mahon Vincent Navarro Michel Le Van Quyen The team was supported by: Emergence (UPMC), Fondation de France, Fondation pour la Recherche Médicale, OCIRP

Team: “NEUROGENETICS AND PHYSIOLOGY” Bertrand Fontaine Cécile Delarasse Sophie Nicole Mohamed El Behi Bruno Eymard Isabelle Rebeix Laure Strochlic

The team was supported by: Agence Nationale de Recherche, Assistance Publique-Hôpitaux de Paris, Association Française de l’Hémiplégie Alternante, Association contre les Myopathies, ARSEP - Aide à la Recherche sur la Sclérose en Plaques, Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres maladies du motoneurone, Fondation de France (Prix Bouvet- Labruyère-ICM 2013), Fondation Maladies Rares, OSEO (defi), BIOGEN, OCIRP, Pharnext

TEAM: “GENETICS OF EPILEPSY” Stéphanie Baulac Sarah Weckhuysen Eric Leguern Michel Baulac The team was supported by the: Agence Nationale de Recherche, Fédération pour la Recherche sur le Cerveau, Ligue Française contre l’Epilepsie, BIOCODEX

TEAM: “CORTEX AND EPILEPSY” Richard Miles Desdemona Fricker Michel Le Van Quyen The team was supported by the: Agence Nationale de Recherche, Inserm (contrat d’interface), Ecole des Neurosciences Paris Ile de France (doctoral contrat), European Commission, Fondation Française pour la Recherche sur l’épilepsie, Fondation pour la Recherche Médicale, OCIRP

TEAM: “OPTOGENETIC DISSECTION OF SPINAL CIRCUITS UNDERLYING LOCOMOTION” Claire Wyart Pierre-Luc Bardet Hugues-Pascal Mousselard The team was supported by the: Ecole des Neurosciences Paris Ile de France (contrat doctoral), Ville de Paris, European Commission, Fondation Campus Paris Saclay, The Human Frontier Science Program Organization, EMBO, Wings for Life, SERVIER, CARCEPT PREV, Fondation Bettencourt Schueller, Philippe Foundation

10 ICM ANNUAL REPORT 2014 TEAM LEADERS PRINCIPAL INVESTIGATORS

AXIS: “DEVELOPMENT, GLIAL PATHOLOGY, AND REPAIR”

Team: “NEUROGENETICS AND PHYSIOLOGY” Bertrand Fontaine Cécile Delarasse Sophie Nicole Mohamed El Behi Bruno Eymard Isabelle Rebeix Laure Strochlic

TEAM: “CELLULAR AND MOLECULAR MECHANISMS IN THE DEVELOPMENT OF GLIOMAS”

Emmanuelle Huillard The team was supported by: INSERM ATIP Avenir, European Commission, Association pour la Recherche sur le Cancer, La Ligue Nationale contre le Cancer

TEAM: “MECHANISMS OF MYELINATION AND REMYELINATION IN THE CENTRAL NERVOUS SYSTEM” Catherine Lubetzki Anne Desmazières Bruno Stankoff Nathalie Sol Foulon

The team was supported by the: Agence Nationale de Recherche, 2ème contrat (PI Catherine Lubetzki) : 1er Mars 2013-29 Août 2016 (84 976e en 2014), Inserm (contrat d’interface), Aide à la Recherche sur la Sclérose en Plaques, Multiple Sclerosis International Federation, Genzyme, VERTEX, MERCK SORONO, Prix Marie-Ange Bouvet Labruyère, NOVARTIS

TEAM: “MOLECULAR AND CELLULAR APPROACHES TO MYELIN REPAIR”

Anne Baron Van Evercooren Violetta Zujovic Brahim Nait Oumesmar The team was supported by the: Agence Nationale de Recherche, INSERM-ITMO Aviesan, UPMC (achat gros équipement), Ecole des neurosciences Paris Ile de France, RTRA-Ecole des neurosciences Paris Ile de France (achat gros équipement), Aide à la Recherche sur la Sclérose en Plaques, ELA research foundation, Fondation Cluny, Fondation pour la recherche sur le Cerveau, Fondation pour la Recherche Médicale, Institut de Recherche sur la Moelle Epinière et l’Encéphale, Multiple Sclerosis International Federation, National Multiple Sclerosis Society via Fondazione Centro San Raffaele, National Multiple Sclerosis Society via Rutgers University, OCIRP

TEAM: “EXPERIMENTAL NEURO-ONCOLOGY” Marc Sanson Ahmed Idbaih Jean-Yves Delattre Khe Hoang-Xuan The team was supported by the: Inca Groupement d’Intérêt Public Canceropôle, La Ligue Nationale contre le Cancer, Fondation pour la Recherche Médicale, Association pour la Recherche sur le Cancer, Beta Innov

TEAM: “OLIGODENDROCYTE DEVELOPMENT AND NEUROVASCUAR INTERACTIONS” Jean-Leon Thomas Michel Mallat Bernard Zalc Carlos Parras Charles Felix Calvo The team was supported by the: Agence Nationale de la Recherche, Agence Nationale de Sécurité Sanitaire de l’Alimentation de l’Environnement et du Travail, Aide à la Recherche sur la Sclérose en Plaques, National Multiple Sclérosis Scoiety via Children’s national organisation, Novartis Pharma, TEVA

ICM ANNUAL REPORT 2014 11 ORGANIZ ATION OF RESEARCH IN THE ICM

TEAM LEADERS PRINCIPAL INVESTIGATORS

AXIS: “COGNITION, EMOTION, ACTION”

TEAM: “PICNIC LAB: PHYSIOLOGICAL EVALUATION IN HEALTHY SUBJECTS AND PATIENTS WITH COGNITIVE DISORDERS” Paolo Bartolomeo Jaccobo Sitt Laurent Cohen Lionel Naccache The team was supported by: Agence Nationale de Recherche, INSERM, Ecole des neurosciences Paris Ile de France (contrat doctoral), European Commission, Fondation Voir et Entendre, Association France Alzheimer, Fondation pour la Recherche Médicale, LesHanot Haim Foundation, McDonnell Foundation, AXA Research Fund

TEAM: “FRONTLAB - FRONTAL SYSTEMS: FUNCTIONS AND DYSFUNCTIONS” Bruno Dubois Michel Thiebaut De Schotten Richard Lévy Antoni Valerocabre Emmanuelle Volle Benedicte Batrancourt Marc Teichman Harald Hampel The team was supported by the: Agence Nationale de Recherche, Ecole des Neuroscience Paris Ile de France, European Commission, ICM, NIH, PIR,Fondation pour la Recherche Médicale, PSP, ERDF France, AXA, Pfizer AVID, ROCHE

TEAM: “STUDY OF EMOTIONS AND SOCIAL INTERACTIONS”

Nathalie George Stéphanie Dubal Philippe Fossati Bruno Millet The team was supported by the: Agence Nationale de Recherche, Institut National de l’Environnement Industriel et des Risques Institut de recherche biomédicale des armées, Fondation pour la Recherche Médicale, Fondation de France, Fondation RATP

TEAM: “BEHAVIOR, EMOTION, AND THE BASAL GANGLIA” Luc Mallet Éric Burguiere Jérome Yelnik Karim Ndiaye The team was supported by the: Agence Nationale de Recherche, Fondation Fondamentale, Christian Poquet

TEAM: “BIOLOGICAL, PSYCHOLOGICAL, AND COMPUTATIONAL BASES OF MOTIVATION”

Sébastien Bouret Jean Daunizeau Mathias Pessiglione The team was supported by the: Ville de Paris, Direction Générale pour l’Armement, European Commission, Fondation Coopérative scientifique Sorbonne Université, Fondation pour la Recherche Médicale, SERVIER

12 ICM ANNUAL REPORT 2014 TEAM LEADERS PRINCIPAL INVESTIGATORS

AXIS: “MODELS AND METHODS FOR NEUROSCIENCE” (TRANSVERSAL AXIS)

TEAM: “ARAMIS: MATHEMATICAL MODELS AND ALGORITHMS FOR IMAGE AND SIGNAL PROCESSING IN THE HUMAN BRAIN”

Olivier Colliot Marie Chupin Didier Dormont Mario Chavez Stanley Durrleman Yves Sanson Damien Galano Dominique Hasboun Sophie Dupont Fabrizio Devico Anne Bertrand The team was supported by the: Agence Nationale de Recherche, European Commission, Fondation Plan Alzheimer (projet CATI, multi-tutelles)

TEAM: “BIOTECHNOLOGY AND BIOTHERAPY” Philippe Ravassard Rolando Meloni The team was supported by the: Agence Nationale de Recherche, Région Ile de France, European Commission, Fondation pour la Recherche Médicale

ICM ANNUAL REPORT 2014 13

2014 IN REVIEW

ICM ANNUAL REPORT 2014 15 RESEARCH RESEARCH

1 Neurodegenerative diseases 2 Multiple sclerosis 1 3 Brain tumors

4 Epilepsies

5 Cognition, behavior, and psychiatric diseases

6 Modeling

7 Rare diseases

8 Basic mechanisms underlying the development and function of the nervous system

Glossary

Over the course of the year, the 600 researchers, engineers, and technicians of the Institute were mobilized to try to find new therapeutic avenues to better understand and treat the diseases of the brain and spinal cord. This chapter will present the major advances made by the teams.

ICM ANNUAL REPORT 2014 17 NEURODEGENERATIVE DISEASES RESEARCH 1 1 NEURODEGENERATIVE DISEASES

Neurodegenerative diseases, like order to detect these diseases early in Alzheimer’s disease, Parkinson’s patients. disease, and Amyotrophic lateral scle- Neuronal death can affect different rosis are chronic and often disabling. regions of the brain associated either These diseases present a problem with intellectual and emotional func- for public health because of patients’ tions, such as in Alzheimer’s disease handicaps, impact on their families, and Creutzfeldt-Jakob disease or with and the cost of care, particularly in view motor system function (Parkinson’s of an aging population. disease, Amyotrophic lateral sclerosis or Charcot disease). What are the genetic and environ- The great challenge for neurodege- mental bases of these disorders and nerative diseases is to develop treat- what determines their progression? ments that stop their progression. What mechanisms are responsible Researchers in the ICM work at diffe- for progressive and selective neuro- rent scales to address this challenge, nal loss? How can one recognize and from identification of diseases in simple distinguish among these diseases at an models in the laboratories to thera- early stage? peutic trials in patients in the Clinical To answer these questions, the teams Investigation Center of the ICM. of the ICM are working to determine the Because of the excellence of ICM molecular bases of certain hereditary researchers and clinicians, this rich forms of these diseases and identify scientific environment benefits patients the most frequent risk factors. They are fully through the development of perso- also identifying biological markers in nalized medicine adapted to each case.

1. Alzheimer’s disease and other pathologies that cause intellectual disability

With about 860,000 people in France Alzheimer’s disease is characterized and 35 million people worldwide who by the slow degeneration of neurons, suffer from Alzheimer-type dementias, beginning with the hippocampus then Alzheimer’s disease is at the center of expanding to other regions of the brain. our attention. This degeneration is the result of the

18 ICM ANNUAL REPORT 2014 concomitant progression of two types propagation of prions and, more of damage, the abnormal accumula- precisely, the conversion of normal tion outside nerve cells of a protein proteins into toxic malformed proteins called ß-amyloid peptide (Aß-peptide) that accumulate and cause neuronal leading to the formation of “amyloid death. The researchers have deve- plaques,” also called “senile plaques,” loped methods for amplifying the and the abnormal accumulation of the malformed proteins in vitro in order tau protein in neurons, leading to their to observe the process of misfolding degeneration and simultaneous cogni- (abnormal folding of the proteins) and tive deterioration. understand the mechanisms of neuronal death. These methods permit the study of the mechanisms of propaga- Understand the mechanisms tion and also allow modeling of the barriers to prion transmission3 and As in many neurodegenerative diseases, also to test therapeutic molecules and lipid metabolism plays a central role in develop diagnostic approaches with Alzheimer’s disease. In 2014, Stéphane excellent sensitivity and specificity4. Haïk and Marie-Claude Potier ’s team The phenomenon of propagation has showed that the increase in membrane been observed in other neurodegene- cholesterol in neuronal cultures led rative diseases, and studies are under- to an increase in the production and way to transfer these findings to other secretion of amyloid peptide, replicating proteinopathies of the central nervous early changes observed in Alzheimer’s system, neurodegenerative diseases 1 disease . These observations have characterized by the abnormal accu- opened new avenues for understanding mulation of certain proteins that include the mechanisms of Alzheimer’s disease Alzheimer’sDisease (aggregation of and identificationof therapeutic targets. ß-amyloid and Tau) and Parkinson’s Disease (aggregation of α-synuclein). In the team of Stéphane Haïk and Understanding this represents a major Marie-Claude Potier, Benoît Delatour challenge: try to block propagation and his collaborators showed that and find treatments adapted to these when amyloid peptides are injected pathologies. into normal mice, they diffuse rapidly in the brain and induce transitory cogni- Cécile Delarasse, from the team of tive deficits. These results confirm in Bertrand Fontaine and Sophie Nicole, vivo the toxicity and pathogenicity of studies the role of the purinergic the Aß-peptides, which will be a prime receptor P2X7R in Alzheimer’s Disease. therapeutic target2. This receptor is implicated in the matu- ration of the precursor of the ß-amy- The team of Stéphane Haïk and Marie- loid protein. When activated, it cleaves Claude Potier studies both Alzheimer the ß-amyloid protein in the middle of disease and prion diseases such as the sequence of the Aß peptide, which Creutzfeld-Jakob disease because prevents the formation of neurotoxic Aß of their important biological analo- peptides and produces a soluble frag- gies. They are interested in the mole- ment that has neuroprotective proper- cular mechanisms implicated in the ties. P2X7R is also implicated in the

ICM ANNUAL REPORT 2014 19 NEURODEGENERATIVE DISEASES RESEARCH 1

release of pro-inflammatory factors by his colleagues demonstrated a correla- microglial cells, innate immune system tion between the presence of a muta- cells present in the brain. An excessive tion in the ABCA7 gene and Alzheimer’s inflammatory reaction can be harmful. Disease6. The ABCA7 protein is strongly P2X7R, because of its role in inflamma- expressed in the central nervous system tion and the cleavage of the ß-amy- and belongs to the family of proteins loid protein, could have a double effect implicated in membrane transport. in Alzheimer’s disease depending on An alteration in the gene encoding this the stage. Cécile Delarasse’s project protein is a risk factor for Alzheimer also aims at understanding the role of disease. These studies open the way for microglial cells, potential targets for new methods for diagnosing Alzheimer the treatment of Alzheimer’sDisease. disease as well as other neurodegenerative disorders.

Identify risk factors Recently, Harald Hampel and his collea- People with trisomy 21 have a higher gues demonstrated that interactions risk of developing Alzheimer’s Disease; between two genes (APOE and PICALM) approximately 45% of people with are associated with both brain atrophy trisomy 21 have an Alzheimer’s-type and cognitive deterioration in patients dementia by age 60. In these patients, with Alzheimer’s Disease7. the protein DYRK1A encoded by a gene on chromosome 21, is overexpressed in the brain. In 2014, the team of Marie-Claude Potier showed that this Visualize the inside of the brain protein is also overexpressed in the The team of Stéphane Haïk and Marie- brains of patients with Alzheimer’s Claude Potier developed CLARITY, a Disease5. The protein could thus be both method that allows visualization of an early marker of and a risk factor the inside the brain of patients with for Alzheimer’s Disease. In collabora- Alzheimer’s disease in 3-D8. This tion with Bruno Dubois, clinical trials technique, applied for the first time are underway in the INSIGHT cohort to samples of brain from patients to determine whether the variation with Alzheimer’s disease from the in expression of this protein appears brain bank of the Salpêtrière Hospital before patients show symptoms and GIE NeuroCEB directed by Charles whether this could be used as a predic- Duyckaerts, permits the study of the tive marker of the disease. organization of senile plaques, axon In a study of 2600 Islanders, Harald trajectories, and neurofibrillary dege- Hampel, in Bruno Dubois’ team, and neration on brain slices.

20 ICM ANNUAL REPORT 2014 Redefine disease criteria connectivity using novel methods of neuroimaging new Since 2007, Bruno Dubois, in collabora- advanced to discover makers tion with a group of international experts specific to the different stages (International Working Group, IWG), is of Alzheimer disease such as damaged trying to define the diagnostic crite- nerve networks. These markers, specific ria for Alzheimer’s Disease in order to to the patient at a given moment, could early detection effective better identify the disease’s different enable the and treatment forms and integrate biomarkers in diag- of Alzheimer disease. nosis. In 2014, the investigators refined 9 diagnostic criteria to improve detection Test treatment efficacy of Alzheimer’s based on physiopathological biomarkers, including quantifica- The team of Bruno Dubois measured the tion of ß-amyloid deposits by PET-SCAN effect of a pharmacological agent, done- and their amount in the cerebrospinal pezil, on the size of the hippocampus in fluid. They have also defined specific patients with Alzheimer’s disease using criteria for atypical forms and preclini- a new technique of image analysis deve- cal stages of Alzheimer’s Disease. loped by the team of Olivier Colliot and Didier Dormont. This clinical study of more than 200 patients from 28 centers throughout France showed that treat- Follow the evolution of disease ment for a year reduced hippocampal In 2014, the collaborative research atrophy in the patients by 45%9. This is performed by Harald Hampel and the first large scale multi-centrer study Michel Thiebaut de Schotten in the team of a treatment in patients with mild of Bruno Dubois was honored by the cognitive deficit and also the first time review Alzheimer’s & Dementia.10 They that a statistically significant effect of a work on early markers of Alzheimer treatment on hippocampal atrophy has disease and measures of brain been obtained in patients.

ICM ANNUAL REPORT 2014 21 NEURODEGENERATIVE DISEASES RESEARCH 1

2. Parkinson’s Disease and other pathologies that cause a motor handicap Parkinson’s Disease is the second most before the disease can be detected common neurodegenerative disease. clinically. Parkinson’s affects 1.5% of people With this goal in mind, the team of Alexis over 60 years of age and 4% of people Brice with Suzanne Lesage, is part of over 85. The disease is caused by the an international consortium that has progressive death of neurons in a deep the aim of defining the genetic profile substantia nigra region of the brain, the . of Parkinson’s disease. This project has neurons These , which use the molecule led to the identification of six new risk dopamine to communicate with other factors for Parkinson’s disease12 and neurons, play an essential role in the confirmed the implication of 19 already control of movement. Symptoms of the known genetic risk factors. The analy- disease slowing of gestures include , sis was performed on data from more limbs and trunk rigidity, tremors limb , than 100,000 individuals and repre- gait disorders loss of dexterity, and . sents a major scientific advance in our understanding of the process by which Physicians know partially how to treat the disease appears the motor symptoms of the patients in patients as well with drugs that replace dopamine but do as the development of new therapies. not know how to prevent neuronal death In collaboration with this international itself. Furthermore, neurodegeneration consortium, the team of Alexis Brice has is not limited to dopaminergic neurons also found a correlation between polyge- or the motor system and affects brain nic risk, mutations in several genes, regions other than the substantial nigra. and the age of onset for the disease13. The early forms of Parkinson’s disease are not only caused by the most penetrant mutations, homozygous mutations Identification of genetic factors in PARK2 for example, but can also be Alexis Brice’s group is developing an caused by a polygenic accumulation of integrated approach to Parkinson’s more common and less penetrant muta- Disease using a variety of experimental tions. The identification of polygenic risk methods in vivo and in vitro to investi- facilitates understanding of gene inte- gate from genetic bases of the disorder ractions and interactions of the genes to its physiopathological mechanisms. with their environment in the increased One challenge is to study early stages risk of developing the disease. of the disease in order to find predic- The team of Philippe Ravassard works tive biomarkers such as gene mutations on dopaminergic neurons. Ongoing

22 ICM ANNUAL REPORT 2014 studies in a mouse model aim at deter- contribute to mitochondrial dysfunction mining the role of GPR88, a gene and neurodegeneration in Parkinson’s already implicated in schizophrenia (see disease. V-Cognition), in the motor and non-motor symptoms of Parkinson’s disease. Treat balance and gait disorders

Prevent neurodegeneration Etienne Hirsch and his team also study the death of non-dopaminergic neurons The team of Etienne Hirsch studies in Parkinson’s disease. In Parkinson’s, the progression of lesions caused by symptoms caused by non-dopaminer- neuronal death and tests the protec- gic neurons, such as gait and balance tive effect of various molecules on disorders, are not corrected by treat- dopaminergic neurons. In his team, ment. These symptoms are severe in Stéphane Hunot and collaborators parkinsonian patients and indicate a have identified a small peptide of viral poor prognosis for the evolution of the origin that protects the neurons impli- disease. cated in Parkinson’s disease against degeneration14. This peptide is part of In collaboration with the team of Brian the X protein of the Borna virus, which Lau, they confirmed that the peduncu- infects nerve cells. The X protein inhi- lopontine nucleus (PPN), a region of bits neuronal death to ensure the the brainstem, is implicated in gait survival of the virus. The peptide was control in humans and that stimulation shown to have neuroprotective effects of the PPN reduces gait and balance in mice when administered intranasally. disorders in patients with Parkinson’s 16 This relatively non-invasive method is disease . very promising for future treatments of The clinical Neurology and Neurosurgery neurodegenerative diseases. team of the Pitié-Salpêtrière Hospital The X protein works by protecting followed six patients implanted with mitochondria, which are the “power electrodes in the PPN for deep brain plants” of cells and are essential for stimulation. The double-blind study energy production, which is an essen- showed a decrease in “freezing” and tial physiological process. When mito- falls in three patients and an impro- 17 chondria are altered, axons degenerate vement in their postural control . The and disappear progressively leading patients also described an improvement to neuronal death. Olga Corti in Alexis in their quality of life. These results are Brice’s team has recently descri- tremendously encouraging and open the bed a natural mechanism for protec- way for the development of new treat- ting mitochondria in an experimental ments for severe forms of Parkinson’s model of Parkinson’s disease15. This disease. However, they should be mechanism involves maintenance of regarded with caution because of risks the expression of a mitochondrial related to the technique that were enzyme, called HSD17B10, by Parkin observed during the study. (mutations in the Parkin gene are impli- As a consequence of this study, Marie- cated in parkinsonian syndromes). Loss Laure Welter in Etienne Hirsch’s team of this protective mechanism could obtained a grant from the Michael J. Fox

ICM ANNUAL REPORT 2014 23 NEURODEGENERATIVE DISEASES RESEARCH 1

Foundation to perform a larger scale implicated in sleep20. The team has therapeutic trial targeting the PPN with recently shown that these abnormalities Carine Karachi. can be detected even before symptoms of Parkinson’s disease appear. These Identify predictive and prognostic very particular sleep disorders are markers not only prognostic markers of the evolution of the disease but also The PPN is also implicated in sleep predictive markers that allow a better regulation. The team of Etienne understanding of its physiology. A Hirsch and that of Marie Vidailhet certain number of collaborations have and Stéphane Lehéricy showed that been established with international lesions of the PPN could be implicated teams to identify other risk factors in sleep disorders observed in parkin- implicated in Parkinson disease21. sonian patients18. This discovery is quite interesting because sleep disorders Other structures in the brainstem, characterized by great agitation are in particular the substantia nigra, a part of the early symptoms of patients region that degenerates in Parkinson’s with Parkinson’s disease. disease, have anomalies in pre-sympto- matic carriers of a mutation responsible The team of Marie Vidailhet and for Parkinson diseases22. Stéphane Lehéricy are at the forefront of recent technical advances in magnetic The identification of these predictive resonance imaging (MRI), which allows markers allows researchers to follow diagnosis of parkinsonian syndromes, patients and try to slow the emergence detection of the progression of the of their symptoms. It’s also a way to disease, and understanding the physio- study the compensatory circuits that pathology of movement disorders19. mask symptoms in spite of the lesions. The aim is to detect biomarkers of the Studies using the same strategy are disease to better understand it and underway on the brainstem circuits make diagnoses as early as possible implicated in gait and cognitive disor- thanks to a multimodal physiological, ders in Parkinson’s disease. clinical, and imaging study in patients In collaboration with Jean-Christophe with Parkinson’s disease. Corvol, the team of Marie Vidailhet and The team has made enormous Stéphane Lehéricy are involved at the advances in the understanding of the national level in clinical studies aimed lesions underlying symptoms. With at determining the efficacy of certain new analytical techniques, they have treatments23 or to evaluate the factors detected small abnormalities in the predicting response to treatment24 in locus coeruleus, which is a structure patients with Parkinson’s disease.

24 ICM ANNUAL REPORT 2014 Understanding movement disorders of dystonia by its unique physiopathological mechanisms26 The team of Marie Vidailhet and .Additionally, Stéphane Lehéricy is also interested the team demonstrated an increase in cortico-striatal connectivity in other less frequent diseases that (cortex- affect movement, such as essential basal ganglia) during motor training in a learning task tremor, Gilles de la Tourette syndrome, , which contributes to the consolidation of motor memory 27 dystonia, or mirror movement disor- . der, which are studied from the points Gilles de la Tourette syndrome is of view of the circuits involved and characterized by motor and vocal tics, their physiopathological mechanisms. which can be associated with behavioral Neuronal circuits link both the cerebral disorders, obsessive compulsive disor- cortex and the cerebellum, situated ders, attentional deficits etc., involving at the back of the brain, as well as the motor, emotional, and limbic circuits. cortex and the basal ganglia situated Yulia Worbe and her collaborators have deep in the brain under the cortex. shown not only an alteration in the The team uses an integrated approach connectivity28 of these circuits but also combining genetic, metabolic, physio- a structural anomaly29 at the level of the logical, and behavioral information as sulci. imaging data well as (MRI and MEG, see Patients with congenital mirror move- the technical platforms of the ICM) and ment disorder make involuntary move- clinical examinations . ments on one side of the body that In their group, Cécile Gallea and her reproduce intentional movements collaborators have recently analyzed the made on the other side of the body. implication of the cerebello-thalamo- This disease was identified clinically cortical circuit (cerebellum-thalamus- and genetically by ICM researchers cortex) in essential tremor25. Emmanuel Roze, from the team of Marie Vidailhet and Stéphane Lehéricy, Cortical functions are altered in and Christel Depienne, from the team dystonia, a neurological motor disor- of Alexis Brice. In 2014, different forms der causing abnormal muscle tone. of the disease were characterized and Researchers have identified a genetic mutations were identified in the genes form of dystonia, myoclonic dystonia, responsible for the disease, RAD51 and which is distinguished from other forms DCC30.

ICM ANNUAL REPORT 2014 25 NEURODEGENERATIVE DISEASES RESEARCH 1

3. Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), called excitotoxicity, hypothesized to or Charcot disease, affects the motor be responsible for the degeneration of neurons, neurons in the brain and motor neurons in ALS. Consequently, spinal cord that innervate muscles. system xC- contributes to the toxic acti- Patients with ALS (4/100,000) suffer in vity of microglial cells. Thus, blocking consequence from a progressive motor system xC- might therefore be of thera- handicap that leads to paralysis and peutic interest to slow the progression death in an average of 2 to 5 years after of ALS. the first symptoms appear. In 2014, Gaelle Bruneteau, member of the team of Bertrand Fontaine Slow the progression of ALS and Sophie Nicole, established a link between the overexpression of The team of Séverine Boillée works with the protein Nogo-A and denervation the ICM in its fight against this disease. of muscles in ALS at the level of the This team is particularly interested in neuromuscular junction32. This protein the role of inflammatory processes in could be both a biomarker that facilita- the degeneration of motor neurons. As tes diagnosis of the disease and a thera- in all neurodegenerative diseases, an peutic target. A phase 2 study aimed at immune response is observed in the testing the efficacy and the safety of a central nervous system in ALS. A major monoclonal antibody directed against question is how the immune reaction, Nogo-A is underway in patients with implicated in the defense of the orga- ALS. nism, becomes deleterious and contributes to neuronal death.

Microglial cells and macrophages are Identify risk factors activated over the course of the disease and produce neurotoxic factors impli- The teams of Séverine Boillée and Edor cated in motor neuron degeneration. Kabashi are involved in the search for In 2014, the team of Séverine Boillée new mutations in order to create models demonstrated the role of “system xC-” of ALS and elucidate the mechanisms in the progression of ALS31. System underlying its progression. xC- is a transporter that mediates the In collaboration with an international release of glutamate, an excitatory consortium, Stéphanie Millecamps in neurotransmitter, by microglial cells the team of Séverine Boillée contributed and macrophages. The increase in the to the discovery of a new gene related level of glutamate is related to what is to the immune system and autophagy,

26 ICM ANNUAL REPORT 2014 TBK1, related to the immune system ATXN2 was a risk factor for the and autophagy, implicated in ALS and development of ALS and FTD-ALS. frontotemporal dementias33 (FTD), a Furthermore, the concomitance of neurological pathology frequently asso- repeats in C9orf72 and ATXN2 could ciated with ALS. have an influence on the type of the disease Over the course of the last years, 29 (ALS or ALS-FTD rather than genes have been implicated in ALS, FTD), the age of disease onset, and the life expectancy 38 notably the gene C9orf72 that is the of the patients . most frequent genetic cause of ALS34 35 and frontotemporal dementias (FTD). Understand the mechanisms These 2 studies have led to the defini- and treat disease tion of clinical criteria that allow rapid molecular diagnosis of patients with a The team of Edor Kabashi developed mutation in C9orf72. the first vertebrate animal model of this genetic deficiency, a knock-down of In collaboration with the team of C9orf72 expression in the zebrafish. In Edor Kabashi Séverine , the teams of 2014, the researchers developed a new Boillée Alexis Brice and have deter- zebrafish model in which the SQSTM1 genetic mined the frequency of several gene was inactivated. In this model, causes SQSTM1 , including , in popu- they observed the loss of the fish’s 36 lations of patients with ALS and/or motor functions associated with a defi- 37 FTD . Furthermore, the analysis of cit in motor neurons, which mimics the sections of spinal cord from autopsied symptoms of ALS39. They also showed Stéphanie Millecamps patients allowed that stimulation of autophagy, the Danielle Seilhean and to compare the degradation of abnormal proteins, rees- neuropathological signs associated tablished normal motor behavior in with the presence of these mutations37 . the fish. Autophagy dysregulation may After a study of a cohort of more than thus be involved in ALS. These results 1500 patients, these three teams are very encouraging and might present demonstrated in 2014 that a long therapeutic perspectives for patients glutamine repeat (polyQ) in the gene with ALS.

ICM ANNUAL REPORT 2014 27 MULTIPLE SCLEROSIS RESEARCH 1 2 MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is the number Identify risk factors one cause of severe non-trauma- The team of Bertrand Fontaine and tic handicap in young adults. It affects Sophie Nicole (see also Alzheimer’s 80,000 about people in France (1 in disease, Amyotrophic lateral sclero- 540,000 1000 people), more than sis, and rare diseases) identified five 2.8 million people in Europe, and about new groups of genes associated with worldwide . a predisposition to MS40. These gene networks are involved in the adhesion MS is an inflammatory disease of the and migration of immune system cells, central nervous system in which the the T lymphocytes, in the brain. The immune system, normally implicated in entry of T lymphocytes into the brain is the fight against viruses and bacteria, is a crucial step in the development of MS activated and attacks itself. because these cells are responsible for the destruction of the myelin sheath. By blocking the migration of T lymphocytes In MS, the inflammatory reaction degradation destroys the protective myelin sheath into the nervous system, of favoring that surrounds neuronal projections, the myelin sheath decreases, repair of the myelin sheath resto- the axons. The main role of this protec- and ration of nerve functions tion is to assure rapid conduction of . One of the the nerve impulse so that information gene networks identified in this analysis identification leaving the brain rapidly reaches the is of major interest for the of new therapeutic targets muscles. Myelin also plays an impor- in MS. tant role in maintaining the integrity of the axons. Repeated inflammatory attacks alter the transfer of information Understand mechanisms and cause motor, sensory, balance, The team of Brahim Nait Oumesmar and visual disorders. Although myelin and Anne Baron-Van Evercooren have has the capacity to renew itself - called demonstrated the beneficial effect of remyelination - this process is ineffec- several molecules on myelin repair. tive in MS and decreases as the disease The latest advance was the identifica- progresses. tion of the effect of a pro-myelinating factor called Olig241. Overexpression of ICM researchers are therefore trying this factor stimulates the regeneration to understand the mechanisms of de- of oligodendrocytes, the cells respon- and remyelination, not only to prevent sible for the production of myelin. This destruction of the myelin, but also to discovery could have repercussions stimulate its repair. on the development of therapeutic

28 ICM ANNUAL REPORT 2014 strategies aimed at stimulating repair and recruitment of oligodendrocyte of the damages caused by MS. precursors in demyelinating lesions. The researchers have recently shown The researchers also demonstrated that oligodendrocyte progenitors are the presence of synaptic connections activated, become more motile, and between neurons and oligodendrocyte express inflammatory factors (CcL2 progenitors in demyelinating lesions. and IL1b) that increase their mobi- Their studies indicate that these lization and differentiation during connections control remyelination42 demyelination45. by regulating the state of proliferation of the oligodendrocyte progenitors. In collaboration with the teams of This mechanism allows the process of Brahim Nait Oumesmar and Philippe myelination to adapt to the activity of Ravassard, researchers in the team the neuronal circuit. of Catherine Lubetzki and Bruno Stankoff demonstrated the role of a The researchers also participated in guidance molecule, netrin, in vivo in a the demonstration that the molecule mouse model. This molecule inhibits endothelin43 inhibits remyelination via the recruitment of oligodendrocyte activation of the Notch receptor. These precursors to MS lesions. By blocking studies open the way to a pharmaco- this molecule, the researchers obtained logical approach to remyelination and an acceleration of myelination46. This the identification of new therapeutic research on guidance molecules is targets. extremely important because accelera- The team is also interested in the cellu- tion of recruitment of progenitor cells lar aspects of de- and remyelination and and remyelination permits axon repair demonstrated the contribution of cells during a period of time when the lesions from the peripheral nervous system to are still reversible. remyelination in the central nervous Another research axis of the team of system. Recently, they identified agroup Catherine Lubetzki and Bruno Stankoff of stem cells in the peripheral nervous focuses on the early mechanisms of the system44. These stem cells/progenitors formation of nodes of Ranvier, regions can generate Schwann cells, cells that of the axon that are not myelinated ensure the myelination in the peripheral and which permit rapid conductance nervous system in response to demyeli- of nerve impulses. The researchers nation in the central nervous system. showed that structures called pre-no- These Schwann cells are of interest des, which resemble nodes of Ranvier, because they are not a target of the appear before the beginning of myeli- immune system in MS, thus remyelina- nation47. The aggregation of these struc- tion by these cells could have a benefi- tures along the axon is induced by a still cial effect. unknown factor produced by the oligo- The research of the team of Catherine dendrocytes. These pre-nodes play a Lubetzki and Bruno Stankoff also functional role, accelerating conduc- focuses on the cellular and molecu- tance of the nerve impulse along the lar mechanisms of de-/remyelination, axon. The fact that another element notably those that control the migration in addition to myelin can accelerate

ICM ANNUAL REPORT 2014 29 MULTIPLE SCLEROSIS RESEARCH 1

the nerve impulse is an innovative By combining several MRI techniques concept. A study is underway to deter- and analyzing the functional connec- mine the role of these pre-nodes during tivity of fiber tracts in the brain, the remyelination. researchers showed that certain tracts are particularly disconnected in patients Measure the evolution of the disease with cognitive disorders, notably default The team of Catherine Lubetzki and networks and attentional networks. This Bruno Stankoff wants to measure disconnection is related to neurodege- what cannot be seen by MRI, notably neration in specific regions of the the evolution of the disease. To do this, cortex, which causes the loss of cogni- they developed an innovative program tive faculties49. of multimodal imaging by positron The team also works on a project of emission tomography (PET-SCAN) of imaging specific to neurodegeneration. demyelination/remyelination. A pilot Although MS is a myelin disease, the study was performed with a tracer that degeneration of neurons is what causes attaches to white matter, PIB, labelled the handicap. By using a PET-SCAN with carbon 11 (PIB is also a marker of tracer (flumazenil), the researchers amyloid plaques in Alzheimer disease), were able to quantify and localize followed by a PET-SCAN coupled with neuronal degeneration and measure MRI48. With this method, the kinetics inflammation in patients50, 51. of demyelination/remyelination can be followed and patients identified accor- These methods allow prediction of the ding to their capacity to remyelinate. evolution of patients, understand why This new methodology could serve as a they progress, and evaluate therapies predictive marker for the evolution of targeting remyelination, neurodegene- the disease. ration, or neuro-inflammation.

30 ICM ANNUAL REPORT 2014 3 BRAIN TUMORS

Around 5000 people are diagnosed each Identify the causes and year in France with a primary malignant mechanisms brain tumor . The symptoms depend on Two “rare tumor” networks are coor- the localization of the tumor, its size, dinated by the Neuro-oncology team. and rate of development. Neurons are The first concerns oligodendroglio- not the only cells in the brain. They mas (POLA network) and is coordi- are supported structurally and func- nated by Jean-Yves Delattre. Thanks glial cells oligden- tionally by such as to high-throughput sequencing, drocytes that produce the myelin that research has made great advances in surrounds neurons. Like lymphocytes our understanding of the development of the immune system, glial cells are of tumors and the identification of origin of the most aggressive and the their causes. Working on the largest frequent tumors, lymphomas, and glio- collection of oligodendrogliomas ever mas , respectively. studied by high-throughput technology, the team of Marc Sanson, in collaboration with the group of Richard Houlston Develop diagnostic and prognostic in London and the team of Emmanuelle tools Huillard, recipient of the ATIP/Avenir Working with samples from one of the grant (Inserm and CNRS), confirmed most important brain tumor banks, the the implication of several genes and OncoNeuroTek, directed by Jean-Yves identified new genes, including TCF12 Delattre, the Experimental Neuro- in the development of these oligoden- oncology team of Marc Sanson uses drogliomas54. A mutation in the TCF12 molecular biology to detect genetic gene compromises transcriptional mutations that cause these tumors, activity and is associated with a more analyze their contribution to the progno- aggressive form of the tumor. Sixty sis, or predict response to a treatment, percent of oligodendrogliomas have a providing useful informations for clini- mutation in another gene, CIC, which cians. A molecular prognosis classifi- is a transcriptional repressor. Vincent cation has thus been proposed starting Gleize in Marc Sanson’s team has just from a small number of key alterations, deciphered the mechanism of action of notably in the IDH1 and TERT genes52,53. this gene in tumor cells55. Identifying the The mutation in IDH1 has an additio- mechanism means identifying potential nal interest. The mutations leads to the therapeutic targets. accumulation of a specific metabolite, The other “rare tumors” network D-2HG. In collaboration with the CENIR, concerns primary brain lymphomas the team of Marc Sanson is developing (LOC network) and is coordinated by Khe a diagnostic tool based on the detec- Hoang-Xuan. The team of Khe Hoang- tion of D-2HG by magnetic resonance Xuan showed for the first time speci- spectroscopy. fic mutations in these rare tumors56.

ICM ANNUAL REPORT 2014 31 BRAIN TUMORS RESEARCH 1

This opens perspectives for targeted The aim of the Experimental Therapeutics therapy. platform Gliotex, supported by the Association for Research on Cancer (ARC) and directed by Ahmed Idbaih, is Develop personalized therapies to develop specific treatments accor- In collaboration with the team of Antonio ding to the mutation profile of the tumor Iavarone at Columbia University, the using cell cultures and grafts in mice. team of Marc Sanson characterized The team has tested an inhibitor targe- a cohort of gliomas carrying a highly ting an oncogene, MDM2, that is ampli- oncogenic fusion gene and showed the fied in certain tumors. Cells containing patients with these tumors, although this mutation respond selectively to this rare, can benefit from a specific treat- inhibitor. A phase 1 trial with an MDM2 ment57. This preliminary study has led inhibitor was initiated following this to a clinical trial coordinated by Marc study. This approach inspires hope in the Sanson, which will begin nationally next long term of personalized treatments September then expand to the rest of for every patient based on the genetic Europe. profile of his or her tumor.

32 ICM ANNUAL REPORT 2014 4 EPILEPSIES

Epilepsy is one of the most frequent After the identification of a new gene, neurological diseases, affecting almost DEPDC5, associated with an hereditary 1% of the population. An epileptic form of focal epilepsy, the researchers seizure is a very brief period of abnormal discovered that in certain cases muta- electrical activity in a group of cortical tions in this gene also cause a malfor- neurons. This electrical discharge can be mation of the cortex58. This lesion might circumscribed to a region of the cortex, be due to a somatic mutation that focal epilepsy, or spread throughout the occurs in brain cells during the life of entire cortex, generalized epilepsy. the patient in DEPDC5 in addition to the mutation inherited from the parents. As with other brain diseases, resear- These results are the first example of chers prefer to use the plural in refe- this type of mechanism being described rence to epilepsies defined by a variety in a focal epilepsy. of features that makes their classifi- cation complex: the type of seizure The team of Eric Leguern and Stéphanie (tonic-clonic seizures with a phase of Baulac identified another gene, FIG4, contractions and a phase of spasms-, implicated in a hereditary epilepsy asso- absences in children, partial seizures, ciated with cortical malformations59. etc.), the cause of the epilepsy (tumor, This gene has already been implicated in infection, malformation, metabolism, other pathologies, including a periphe- genetics, etc.), and the association of ral neuropathy (Charcot-Marie-Tooth other neurological signs, such as the disease) and a malformation syndrome profile of the electroencephalogram. in newborns. The team showed that one of these three syndromes will develop, A third type of epilepsy in the population depending on the localization and type resists medical treatment. These forms of the mutation. of epilepsy constitute the main target of Caroline Nava Christel Depienne ICM researchers and clinicians. and , in collaboration with the electrophysiology platform and a European consortium, recently discovered that de novo Identify the responsible genes mutations, not present in the parents, The team of Eric Leguern and of the HCN1 gene are implicated in Stéphanie Baulac are interested in the Dravet syndrome, a severe epilepsy in genetic origins of epilepsies. Their aim newborns60. At first, these children have is to identify new genes responsible recurrent febrile convulsions that resist for hereditary (genetically determined) treatment followed by epileptic seizu- epilepsies and to develop experimen- res that also resist treatment. Towards tal models in vitro and in vivo in order their second year of life, these infants to elucidate the mechanisms of epilepsy develop cognitive disorders. The HCN1 and test new treatments to improve gene is very interesting because it enco- care of the patients. des a protein that contributes to the

ICM ANNUAL REPORT 2014 33 EPILEPSIES RESEARCH 1

formation of a neural channel, the HCN the neurons. Each neuron receives, channel,which controls rhythmic acti- processes, and sends electrical messa- vity of neurons. This discovery confirms ges to other neurons. At this level, the crucial role of HCN channels in certain keys to epilepsy can be found. the mechanisms implicated in human Abnormal electrical activity prevents epilepsies. The discovery of a new gene- information processing in epilepsy, tic cause of this disease will additionally and thus electrophysiological probing help refine diagnosis. can provide keys to understanding the disease. The team of Stéphane Via their participation in the Charpier uses electrophysiology to EuroEPINOMICS consortium, the team study the electrical activity of the brain of Eric Leguern and Stéphanie Baulac, on all spatial scales and in real time, associated with Christel Depienne, from global electrical activity measured also identified another gene implicated on the surface with EEG, to the intra- in severe epileptic encephalopathies, cellular activity of individual neurons. KCNA261. In close interaction with neurologists, The team is also interested in the patho- this team explores both focal and gene- genic mechanisms caused by mutations ralized epilepsies, notably childhood in the Lgi1 gene. In order to determine absence epilepsies. They showed that the population of neurons implicated there are zones of high frequency acti- in focal familial epilepsies caused by vity in the epileptogenic regions of the mutations in Lgi1, the researchers deve- brains of patients with focal epilepsies. loped a mouse model in which the gene These rapid rhythms thus become elec- could be mutated specifically in certain trophysiological markers of an epilepto- subpopulations of neurons. They could genic region because they are specific to thus show that epilepsy is linked to exci- the region in which the seizure begins tatory glutamatergic neurons (neurons and are recorded before the seizure that use glutamate as a neurotransmit- occurs63. This discovery is impor- ter)62 . tant because it provides a link to the mechanisms upstream of the epileptic seizure, which could help researchers understand how to predict and antici- Study the dynamics of the brain pate seizures. The team of Stéphane Charpier studies the dynamics of activity in neuronal Understand the mechanisms networks in the brain and the excitability of individual neurons. Information The team of Richard Miles works on is encoded in the electrical activity of dysfunctions related to focal epilepsies,

34 ICM ANNUAL REPORT 2014 those with a localized epileptic center. human tissues conserve their morpho- The focus is often situated in the hippo- logical characteristics and their campus, a region hidden deep in the epileptic activity for 4 to 6 weeks. The temporal cortex. Richard Miles and maintenance in culture of these cells his collaborators seek to understand enables researchers to transfect them how anomalies of synaptic signaling with viral vectors that express probes of between neurons can lead to epileptic neuronal activity or test the long term activity. effect of treatments. gliomas Brain cancers, or , are often The team of Richard Miles also explo- corti- associated with epilepsy. In the res the sclerosis or neuronal death cal area around the tumor , researchers that causes focal epilepsies. They work detected differences in the expression in particular on the role of lipids in chloride transporters64 of that modify neuronal death, including cholesterol. synaptic signaling in the hippocampus In collaboration with Nathalie Cartier, of patients with focal epilepsies. the team of Richard Miles showed that The team of Richard Miles developed a by inhibiting the extrusion of choleste- technique to maintain slices of brain rol from neurons, epileptic activity and tissues from patients with focal epilepsy neuronal death increase in the hippo- of the temporal lobe in culture65. These campus of mice66.

ICM ANNUAL REPORT 2014 35 COGNITION, BEHAVIOR, AND PSYCHIATRIC DISEASES RESEARCH 1 5 COGNITION, BEHAVIOR, AND PSYCHIATRIC DISEASES

The brain is a astounding machine for is consciousness? How do we commu- processing information, an activity that nicate with language? underlies cognition (perception, reflection, memorization, decisions, speaking, To answer these questions, ICM resear- etc.), from which emerges conscious- chers study how neuronal networks ness of ourselves and the world around perform information processing using us. a variety of tools, from the most subtle The mechanisms that underlie mental clinical analyses to electrophysiologi- functions, whether motor, intellec- cal examination, as well as neuroima- tual, or emotional, are at the origin of ging. The data obtained are essential for human behaviors. Why do we do what understanding and better treating the we do? What are the bases of normal or functions altered in patients, whether altered motivation? How do our inten- they have intellectual (memory loss, tions produce behaviors? How do our language disorders, perceptions, intellectual and emotional functions notably visual, etc.) or psychiatric combine to determine our actions? disorders (depression, anxiety, schizo- How do we become conscious of the phrenia, autism, obsessive compulsive world around us and ourselves? What disorders, etc.).

1. Emotions, depression, and social interactions

The team of Nathalie George and photographs of human faces showing Philippe Fossati is interested in the fear or happiness, negative or positive mechanisms by which social processes stimuli. Anxiety is not simply felt, it also activate and regulate the emotional has an impact on the way the subjects brain. perceive the world. This study opens new avenues understanding of Thanks to the high temporal resolution to the anxiety of magnetoenphalography (MEG), which . operates on the order of the millisecond, A study of epileptic subjects treated and electroencephalography (EEG), the by electrodes implanted in their brain team of Nathalie George and Philippe showed that a region implicated in Fossati showed an early perceptional emotions, the amygdala, is activa- bias in anxious subjects67. These people ted early when the patients look at are hypervigilant and react faster photographs of faces68. These experi- than others when they are presented ments help understand the speed of

36 ICM ANNUAL REPORT 2014 information processing by the “emotio- of depression and will help define new nal brain.” therapeutic targets for this disorder. A meta-analysis performed by the team Bruno Millet, who joined the team of demonstrated the contribution of a Nathalie George and Philippe Fossati region of the brain, the anterior cingu- in 2014, is specialized in deep brain late cortex, to social distress related to and magnetic transcranial stimulation, exclusion. The same region is dysfunc- both of which he uses to treat depres- tional in depressed patients69. This sion that is resistant to pharmacological study underlines the importance of treatments70 and obsessive compulsive social exclusion in the physiopathology disorders71.

2. Autism The team of Nathalie Georges and called the insula, which plays a central Philippe Fossati showed that being role in social behaviors and the deve- imitated improved the social behavior lopment of emotions.72 These results of autistic patients by modulating speci- open new perspectives for the treat- fic egionsr of the brain, notably a region ment of autism.

3. Motivation and decision making

The team of Mathias Pessiglione, or the other of these two aspects of a Sébastien Bouret, and Jean Daunizeau behavior can be preferentially targeted is interested in apathy and thus in the in apathetic patients. motivation processes involved in human . The team of Mathias Pessiglione, Treatments for apathy target dopami- Sébastien Bouret, and Jean Daunizeau nergic and noradrenergic (use nora- demonstrated the effect of context drenaline as their neurotransmitter) on our value judgements74. The region neurons, which play an important of the brain responsible for the attri- role in motivation. To determine the bution of value is the orbito-medial respective roles of these two types prefrontal cortex, which has increased of neurons, the team of Sébastien activation when something pleases Bouret performed a behavioral study. us. An experiment in healthy subjects Motivation determines many aspects showed that when background music of our behavior, including the choice of is agreeable, subjects better appre- our actions and the mobilization of the ciate a painting they are shown. Thus energy needed for these actions. The pleasant music increases the activity researchers showed that dopaminer- of the orbito-medial prefrontal cortex, gic neurons intervene in the decision predisposing the person to appreciate to act, whereas noradrenergic neurons the painting presented. Judgements contribute to the mobilization of the are therefore influenced by context. By energy needed to perform the action73. affecting the state of our orbito-medial This is a major discovery because one cortex, the context will influence our

ICM ANNUAL REPORT 2014 37 COGNITION, BEHAVIOR, AND PSYCHIATRIC DISEASES RESEARCH 1

value judgements. The team was able sites they preferred. Finally, they were to distinguish the main properties required to reconsider the sites. Subjects of the system for attributing values, had a tendency to prefer the sites they which is conserved in primates. This had already chosen and showed less also leads to an increasingly precise preference towards those that they had cartography of the different regions of eliminated. This demonstrated that the the brain implicated in motivation and human beings are in internal conflict decision-making. with themselves; this is called cognitive dissonance, and the best way to Of course, motivation is not localized in resolve this conflict is to change our a region of the brain but emerges from values. To relieve internal conflicts and cooperation among several regions obtain coherence between our values organized in networks. The researchers and our actions, we tend to give more thus invented a mathematical method value to our choices. Thus our values to describe the way that the activity of influence our actions, but, our actions the brain systems are coordinated to also influence our values. We thus have 75 control behavior . Applied to recor- a mechanism for internal coherence dings of brain activity of healthy subjects that is related to the memory of our making a series of decisions, this actions76. method will allow us to both understand how pertinent information is processed Thanks to the PRISME platform (see and transformed through the neuro- Platforms), the team of Bruno Dubois nal networks to produce a behavioral and Richard Lévy (see Creativity and response and also to predict the kinds reasoning) is developing an innovative of functional deficits that are induced by project, EcoCapture, for an ecological lesions of the brain. study of apathy. Using body sensors, the behavior of apathetic patients will The team of Paolo Bartolomeo, be analyzed in a semi-ecological situa- Laurent Cohen, and Lionel Naccache tion. This project will be carried out in (see Language and mechanisms of collaboration with the company ERDF. consciousness) is interested in the way The aim is to use the data obtained to we attribute values and meanings to our allow patients suffering from a neuro- choices. The researchers asked heal- logical deficit, who have disorders of thy subjects to evaluate vacation sites decision-making or behavior, to go back then asked them to choose among the to work.

38 ICM ANNUAL REPORT 2014 4. Creativity and reasoning

Bruno Dubois and Richard Lévy, in their These two mechanisms depend on laboratory FRONTlab, are interested specific regions in the frontal lobes79. in the mental functions of the frontal Creativity is greatly affected in patients lobes. These functions construct and with lesions of the frontal lobe, contrary control our most complex behaviors, to what has been published in the lite- such as decision-making, creativity and rature that suggests that this type of analogical reasoning, the generation of lesion increased creativity. It is thus due voluntary behaviors, and the organiza- to control and the capacity to elabo- tion of language. rate new rules that creativity can be expressed80. In studies of patients with lesions of the These discoveries show the hetero- frontal lobe, the team of Bruno Dubois geneity of the frontal lobe. The aim and Richard Lévy showed that cognitive of the team is to dissect the multiple control in the frontal lobe is organized processes involved in creativity, their hierarchically; a cascade of controls is interrelationship, and the underlying exerted from anterior regions towards brain regions. posterior regions77. The researchers In the team of Bruno Dubois and Richard also related the capacity for analogi- Lévy, Antoni Valero-Cabré, in collabora- cal reasoning with different structures tion with the team of Paolo Bartolomeo of the prefrontal cortex and showed (see Language and Mechanisms of that variability in these capacities is consciousness), uses non-invasive correlated with the volume of certain stimulation to modify the oscillatory subregions of the frontal lobe78. The activity of the frontal lobe and improve researchers in this team showed that visio-spatial cognition in patients with categorization involves distinct func- brain lesions. Studies are underway at tions, both the capacity to collect infor- present in patients with progressive mation and the capacity to abstract. supranuclear palsy (PSP).

5. Language and networks

In the team of Bruno Dubois and Lionel Naccache (see Mechanisms Richard Lévy, Marc Teichman identi- of consciousness) demonstrated the fieda new network linking Broca’s area existence of privileged connections with the basal ganglia, a network that is between the region of letter recogni- critical for the syntactic organization of tion and language areas82. The same language81. small region of the visual cortex in the Using diffusion MRI to trace white left hemisphere enables us to identify matter fibers connecting different the letters we see, thus the anatomy of regions of the brain, the team of Paolo communication pathways in the brain is Bartolomeo, Laurent Cohen, and key for determining brain functions.

ICM ANNUAL REPORT 2014 39 COGNITION, BEHAVIOR, AND PSYCHIATRIC DISEASES RESEARCH 1

6. Mechanisms of consciousness

Paolo Bartolomeo, Laurent Cohen, One of the many signatures of the and Lionel Naccache seek in their level of consciousness is the way in patients, answers to basic questions which regions communicate with each not only concerning visual attention and other85. In 2014, Lionel Naccache and language, but also consciousness. They Laurent Cohen applied for a patent for explore the brain mechanisms and the this discovery. psychological properties of conscious The group of Lionel Naccache recently mental operations . showed in a collaboration why we are Using EEG, they recently identified not conscious of external noises during neuro-markers of levels of conscious- sleep86. They found that even if sounds ness in patients incapable of commu- penetrate the auditory cortex, sleep nicating. Approximately 100 brain disturbs the capacity of the brain to anti- signatures of consciousness have been cipate the sounds. identified, which have permitted distin- The team also studies the question guishing a patient in a vegetative state of conscious perception. The team from a patient with minimal conscious- showed that unconscious treatment of 83 ness . An algorithm integrating all these sounds takes place in auditory areas of signatures makes it possible not only to the temporal lobe, but that conscious- diagnosis predict make a , but also to ness of the regularity of sounds requires the evolution of the patient. This is the communication between different algorithm first time that an has had regions of the brain including the fron- prognostic value . These studies aim at tal lobe87. Another study concerned developing new tools for diagnosing the processing of the meaning of words in level of consciousness of patients who conscious subjects88. The researchers cannot communicate. have also shown that when a person The researchers also detected diffe- is asked to pay attention to something, rent brain signatures of the proces- the person becomes conscious of what sing of the meaning of words. Certain was presented just before. Conscious of these signatures are not conscious perception is thus restrospective89. and can appear if the patient is in a The team of Stéphane Charpier (see specific to a state of coma, others are Epilepsies) studies the mechanisms consciousness84 . underlying consciousness. In a normal Consciousness is not related to the brain, there is a constant background function of a single brain region but activity in each individual neuron called to communication between regions. synaptic noise. In an experimental

40 ICM ANNUAL REPORT 2014 model, the team of Stéphane Charpier background brain activity at the origin completely suppressed this activity of the variability of neuronal responses in the brain, which remains normal to exogenous stimulations (outside from a connectivity point of view. The the brain) is probably related to the brain is then in an isoelectric, electri- mechanisms of consciousness. What cally neutral state, and its response creates the significance of a stimulation to a given stimulation is always iden- is both the stimulation itself and the tical. Consequently, the endogenous endogenous activity of the brain. This activity of the brain (produced by the discovery has led the team of Stéphane brain) creates variability in the way Charpier to begin a study of patients in neurons respond to stimulations90. This deep comas.

7. Clinical cases and compensatory strategies of the brain

The study of patients with neurologi- enable patients to take advantage of a cal dysfunctions permits researchers program of reeducation adapted to the to understand the basic mechanisms disorder, which can become chronic. of brain function and adapt diagnoses. Following a stroke in the right hemis- Another clinical case concerns an phere, certain patients act as if the left extremely rare and formidable gene- side of the world no longer exists; they tic disease, Ondine syndrome, which suffer from unilateral spatial neglect. prevents patients from breathing Some of these patients recover with because of a severe dysfunction of the time, but spontaneous improvement part of the brainstem responsible for of neglect is far from the rule; at least automatic respiration. In the most severe one third of patients in the acute phase forms, the patients die asphyxiated as of this disorder will continue to present soon as they fall asleep. Current treat- signs more than a year after their lesion. ment consists of an external ventila- By following the evolution of 45 patients tor that patients use when they sleep, with this pathology by diffusion MRI, the even during a short nap. When they are team of Paolo Bartolomeo showed that awake, they must breathe voluntarily. the neglect persists when it is asso- The team of Lionel Naccache, Laurent ciated with destruction of the fibers Cohen, and Paolo Bartolomeo perfor- of the corpus callosum that mediate med a study in a young woman awake dialogue between the two brain hemis- and suffering from this syndrome and pheres91. If the fibers aren’t affected, compared brain activity when she either the two hemispheres can compen- breathed voluntarily or with external sate in part for one another thanks to ventilation. The researchers showed mechanisms of brain plasticity, which that she was more effective in carrying are not well known. The identification out intellectual activities with assisted of factors that predict the persistence respiration. Her cortex was available of neglect is an major clinical chal- for other activities when it no longer lenge because this identification would had to manage her respiration 92.

ICM ANNUAL REPORT 2014 41 COGNITION, BEHAVIOR, AND PSYCHIATRIC DISEASES RESEARCH 1

The team of Lionel Naccache, Laurent hemispheres of the brain. A patient with Cohen, and Paolo Bartolomeo also lesions at this level developed the capa- recently demonstrated the existence city to transfer information through the of a new pathway for the treatment of anterior region of the brain, the frontal visual information by the brain93.The lobe, which is not normally implicated in posterior part of the corpus callosum this type of activity. transfers information between the two

8. Obsessive compulsive disorders

The team of Luc Mallet is specia- behaviors. The objective is to better lized in the study of the basal ganglia, identify the brain circuits at the origin a group of deep subcortical regions of of the symptoms of the OCD and better the brain. The team showed the impli- understand the origin and the functio- cation of one of these regions, the nal relationship between compulsions subthalamic nucleus, in a pathological and obsessions. These complementary behavior, obsessive compulsive disor- approaches allow adapting different der (OCD)94. Patients with this disorder therapeutic strategies according to the suffer notably from the need to reassure neurobiological origin of this disorder, themselves repeatedly and exagge- which is inaccessible to classical clinical ratedly with respect to their acts (“Did approaches. I turn off the gas?” etc…).The results of Overall, the aim of these translational the team confirmed that this region is approaches is to better understand the a good target for therapeutic stimula- mechanism of action of brain stimulation tion. With the recent recruitment of the and optimize the safety of this procedure researcher Eric Burguière, the team in patients. At the therapeutic level, the set up a translational approach using team, a recognized leader in the field, experimental models of this pathology, recently completed a comparative study in which they can use optogenetics to of stimulation targets in patients with specifically modulate the activity of severe OCDs and began a clinical study neurons implicated in the compulsive of severe cocaine addiction.

42 ICM ANNUAL REPORT 2014 9. Schizophrenia

The team of Philippe Ravassard and schizophrenia, normalizes cognitive Rolando Meloni studies schizophrenia, behaviors in a model of schizophrenia. a severe and disabling mental disease These behaviors are resistant to treat- that affects about 1% of the population. ments commonly used in patients. This The team has recently identified a new study represents an important advance therapeutic target for the treatment in the validation of a new therapeu- of this disease95, the receptor Gpr88, tic target and an innovative experi- present on the surface of cells and mental approach. For these studies, localized exclusively in the brain. The Manuela Ingallinessi was awarded the researchers showed that local inactiva- Louis FOREST Life Sciences thesis tion of Gpr88 in the nucleus accumbens, prize offered by the Chancellery of the situated in the ventral striatum, a struc- Universities of Paris. ture the function of which is altered in

ICM ANNUAL REPORT 2014 43 MODELING RESEARCH 1 6 MODELING

Different imaging techniques (EEG, used in a clinical study of this magni- MEG, MRI) are complementary, but their tude (see Alzheimer’s disease). integration is difficult because of their The researchers also developed a heterogeneity. Integration is a problem model that enables understanding of for all data obtained in patients. One of the organization of the brain by graph the challenges for the team of Olivier theory97. This model provides neuros- Colliot and Didier Dormont is to cience researchers with practical infor- combine this varied and complex data mation for the study of brain networks. in a form that is useful for research, a In collaboration with the team of contemporary problem typical of “Big Claire Wyart, Fabrizio De Vico Fallani Data” produced by the new digital tech- developed a mathematical model to nologies. The ARAMIS team was created characterize neuronal networks in the in 2013. Because of its unique thema- zebrafish98 (see Basic mechanisms). tic situation in the Institute, it is a joint This effective method is useful for team with Inria (National Institute for studying functional abnormalities in the Research in Informatics and Applied nervous system during development or Mathematics). More generally, the aim under pathological conditions. of the team is to develop better methods of image analysis to characterize the A new statistical method was developed numerous neurodegenerative diseases to analyze grey matter and white matter (Alzheimer’s disease, frontotemporal tracts simultaneously in the brain. With dementia, etc.), epilepsy, and cerebro- this tool, variations in connectivity as vascular pathologies (vascular demen- a function of the morphology of the tia, stroke). brain can be visualized. In collaboration with the team of Marie Vidailhet With new image analysis technology and Stéphane Lehéricy, the resear- developed by the team, the researchers studied patients with Gilles de la chers were able to measure the effect Tourette syndrome and confirmed in of a pharmacological agent on the size vivo the presence of abnormal connec- of the hippocampus in patients with tions between the central grey matter Alzheimer’s disease in collaboration and the cortex99 (see Parkinson’s with the team of Bruno Dubois96. This disease and other pathologies that is the first time that this technology was cause motor handicaps).

44 ICM ANNUAL REPORT 2014 7 RARE DISEASES

Several teams in the ICM are mobilized disease, cerebellar ataxias, spastic in the fight against rare neurodege- paraplegias, channelopathies, and nerative diseases such as Huntington alternating hemiplegia of childhood.

1. Huntington disease

Huntington disease is a neurodege- A study on 10 patients with Huntington nerative disease linked to a genetic disease showed that this treatment mutation. The signs of the diseases improves brain energy metabolism, often develop in people between 30 which is abnormal in patients and and 50 years old with the appearance contributes to the progression of their of progressive motor, behavioral, and symptoms100. This result represents a psychiatric disorders, which lead to major advance for the discovery of new dependency and affect the rest of the treatments and a license was obtained family. , Even though the genetic anomaly from ULTRAGENYX, the company that was discovered in 1993, there is still no commercializes triheptanoin. On the treatment that can change the course of basis of these results, a one-year clinical the disease. In the team of Alexis Brice, study has been initiated in France and Fanny Mochel and Alexandra Dürr have the Netherlands on about one hundred recently demonstrated the therapeutic patients using clinical parameters and potential of a synthetic oil, triheptanoin. imaging as evaluation criteria.

2. Cerebellar ataxias

Research on the spinocerebellar the team of Alexis Brice contributes. ataxias (SCA), which interests the Alexandra Dürr, Giovanni Stevanin, team of Alexis Brice, has made major and their colleagues of the internatio- advances this year. A neurodegenera- nal SPATAX network helped identify tive disease of the cerebellum that is two new genes that are responsible for characterized by specific motor symp- autosomal dominant forms of spinoce- toms such as balance disorders, SCA rebellar ataxia when mutated. can be very disabling . SCA are caused One of these genes, ELOVL5/SCA38101, in half of cases by mutations in about encodes an enzyme involved in lipid thirty genes, but many cases cannot yet metabolism, opening the way for a be explained. diagnosis by assay of polyunsaturated The advances are the result of ambi- fatty acids in the plasma of patients. tious international projects to which The second gene, TMEM240/SCA21,102

ICM ANNUAL REPORT 2014 45 RARE DISEASES RESEARCH 1

encodes an membrane protein that is Giovanni Stevanin, the analysis of abundant in synapses, though its role genetic data from the largest cohort is unknown. Mutations in this gene ever studied in the field of SCA (1931 are associated with complex phenoty- patients), a correlation was discovered pes including cognitive dysfunction or between the age at which SCA appears slowly evolving mental retardation. The and a trinucleotide (CAG) repeat in diffe- discovery of these genes represents rent genes105. This discovery is a step hope for the identification ofnew poten- further in our understanding of SCA. tial therapeutic targets. The identification of genes that can modulate the severity of the patho- In a genetic study of 144 patients with logy (age of symptoms onset, asso- congenital ataxia, Alexandra Dürr and ciated signs, rate of deterioration, etc.) her collaborators also showed that could permit the application of alter- different mutations in the GRID2 gene, native therapeutic strategies aimed at which encodes a glutamate receptor, are slowing the progression of the disease. implicated in the development of more In a large cohort of patients with SCA or less severe cerebellar ataxias103. (types 1, 2, 3 and 4), Fanny Mochel and Finally, a gene responsible for a severe her collaborators identified early brain form of the disease associating ataxia energy dysfunctions by MRI spectros- and dystonia was identified in one family copy that were correlated with clinical by the group of Giovanni Stevanin in parameters106. The analysis of an experi- collaboration with a team of the AFM104. mental model and the brains of patients The protein encoded by this gene inte- with a severe form of ataxia associated racts with a major gene implicated in with retinal degeneration enabled the dystonias, establishing a link between group of Annie Sittler to show that the these rare diseases. pathogenesis could be explained in part In a vast international study asso- by an alteration in the pathways invol- ciating 12 countries (EUROSCA and ved in the degradation/recycling of NEUROMICS projects) piloted by proteins107.

3. Spastic paraplegias

Hereditary spastic paraplegias are disorders due to stiffness, or spasticity, clinically and genetically heteroge- of the lower limbs. neous neurological disorders that The team of Alexis Brice participated affect people of all ages. The clinical in an international study that led to the signs appear progressively and are identification of 18 new genes impli- characterized by severely disabling gait cated in hereditary spastic paraplegias

46 ICM ANNUAL REPORT 2014 (HSP)108. This study is based on the initial new gene, REEP2, implicated in HSP. genetic analysis of 55 families from This gene encodes a protein in the several countries and 200 families from endoplasmic reticulum, a network of the SPATAX network as well as models intracellular membranes with various of the effects of the mutations in the functions including the synthesis of zebrafish and a bioinformatics analysis proteins and lipids and the production of that showed interconnections between membranes. The REEP2 gene increases these genes and more than 500 other the number of genes implicated in genes. This study brings the number of HSP in relation to the functions of the genes potentially mutated in HSPs to 74. endoplasmic reticulum, underlining the These discoveries will lead to the iden- importance of this intracellular network. tification of new cellular mechanisms The aim of the researchers is to better implicated in the development of the understand the correlation between disease and new potential therapeutic the anomalies of the endoplasmic reti- targets. culum and neurodegeneration in order to develop therapeutic strategies that Frédéric Darios, Giovanni Stevanin, could be common to several forms of and their collaborators discovered a HSP.

4. Diseases of neuromuscular excitability

Congenital myasthenic syndromes are already allowing a molecular diagno- a group of genetic disorders that disrupt sis and the possibility of new therapeu- the functioning of the neuromuscu- tic approaches. This publication also lar junction, the zone of communi- opens the way to more basic research cation between the motor nerve that on the mechanisms of action of agrin commands a movement and the muscle in the pre- and postsynaptic compart- on which it acts. These syndromes are ments upstream and downstream of the characterized by muscle weakness that synapse. affects, depending on the form, the Muscle channelopathies constitute trunk, the limbs, or the face, notably another heterogeneous group of genetic with ocular problems. The most severe disorders that are associated with muta- forms cause motor or respiratory defi- tions in genes encoding ion channels. cits requiring mechanical ventilation. The ion channels that are altered in The team of Sophie Nicole and Bertrand muscular channelopathies are voltage- Fontaine has shown that mutations in dependent channels, channels that are the agrin gene are responsible for a form sensitive to variations in membrane of congenital myasthenic syndrome potential. Voltage-dependent ion characterized by weakness and atro- channels play a determining role in the phy of the distal muscles109. Agrin plays contraction and relaxation of muscles. an important role in the formation Muscle channelopathies are charac- and maintenance of the neuromuscu- terized by attacks of muscle stiffness lar junction. This discovery has major (non-dystrophic motonia) or paraly- implications for the care of patients, sis. The diagnosis is complicated by

ICM ANNUAL REPORT 2014 47 RARE DISEASES RESEARCH 1

the periodic nature of the symptoms, encoding the muscle chloride channel, but is important for the prevention of at the origin of a form of congenital the disease because certain factors motonia, can modify the phenotype of can worsen the attacks. The team has motonia caused by mutations in the also shown that mutations in the gene muscle sodium channel.110

5. Alternating hemiplegia of childhood The team of Sophie Nicole and Bertrand Nicole and Bertrand Fontaine showed Fontaine is interested in another rare that a mutation in the ATP1A3 gene is disease, alternating hemiplegia of not the only determinant of clinical signs childhood. This neurodevelopmental of the disease and can lead to dystonia disease is characterized by periodic parkinsonism or alternating hemiple- hemiplegia and paroxystic disorders, gia of childhood in different individuals persistent developmental retardation, in the same family. This implies that in and a cognitive deficit. The disease addition to genetic factors, epigene- appears before 18 months of age. tic and environmental factors play an The earliest sign is the occurrence of essential role in the expression of the repeated episodes of hemiplegia lasting clinical symptoms113. Altogether, these a few minutes or several days, affecting discoveries have led to both the deve- one side or the other. An internatio- lopment of a genetic diagnostic tool for nal collaboration among researchers, alternating hemiplegia of childhood and clinicians, and patient associations has also to the possibility of new therapeu- led to the identification of mutations in tic strategies. the ATP1A3 gene responsible for the The researchers also showed that a disease111. This gene, mutated in 75% special diet decreased the frequency of cases of alternating hemiplegia of and the severity of the paroxysmal childhood, encodes the alpha subunit attacks associated with the disease114. of a sodium/potassium pump expressed in neurons, which plays a major role in These results are very encouraging and the regulation of neuronal excitability open the way to other energy-related and is also responsible for rapid onset therapeutic approaches like those of dystonia parkinsonism112. In collabora- Emmanuel Flamand-Roze in the team tion with the team of Marie Vidailhet and of Marie Vidailhet and Fanny Mochel in Stéphane Lehéricy, the team of Sophie the team of Alexis Brice.

48 ICM ANNUAL REPORT 2014 8 BASIC MECHANISMS UNDERLYING THE DEVELOPMENT AND FUNCTION OF THE NERVOUS SYSTEM

Understanding the basic mechanisms and the prevention of the appearance of of the development and functioning of neurological diseases. the normal nervous system is necessary for the detection of abnormalities 1. Glial cell development

The research of the team of Jean-Léon demyelination is due to oligodendrocyte Thomas and Bernard Zalc concerns precursors residing in the nerve, which the development of glial cells. Glial are responsible for remyelination115. assist neurons cells the of the central Carlos Parras has shown the contribu- nervous system (CNS) structurally and tion of the transcription factors Olig2 functionally and are extremely hetero- and Mash1 to the development of oligo- geneous. The most immature are the dendrocytes and the process of demyeli- neural stem cells that produce neurons, nation116,117 . astrocytes, and oligodendrocytes, the myelinating cells of the central nervous Charles-Félix Calvo has established the system. Astrocytes and oligodendro- importance of a molecule, VEGFR3, in cytes are differentiated cells derived the activation of neural stem cells and from neural stem cells. A third popula- consequently the production of new 118 tion of glial cells in the central nervous neurons . This molecule is the receptor system consists of microglial cells, for a growth factor (VEGF). Throughout which are non-neural in origin and infil- life, an adult is able to generate new trate into brain tissue. neurons from neural stem cells in order to maintain cognitive function. This neuro- The aim of the team is twofold: on the genesis takes place in the hippocampus, identify molecules necessary one hand, a structure of the brain that plays a for the production, maintenance, and central role in memory. Experiments differentiation of stem cells and glial in vivo in a mouse model confirm that cells, and on the other hand, test the VEGFR3 signaling specifically activates therapeutic potential mole- of these neural stem cells in the brain. It not only cules in models of developmental and participates in but is absolutely neces- neurodegenerative diseases and during sary for the “awakening” of the neuro- aging. nal stem cells and thus the creation of Michel Mallat and Bernard Zalc studied new neurons without provoking vascular the process of de-/remyelination of the proliferation. These results, reproduced optic nerve in Xenopus and showed in vitro in human cells, bring new hope that the response of microglia to for the development of therapies that

ICM ANNUAL REPORT 2014 49 BASIC MECHANISMS UNDERLYING THE DEVELOPMENT AND FUNCTION OF THE NERVOUS SYSTEM RESEARCH 1

improve the production of neurons to The team has also collaborated in seve- alleviate cognitive decline in persons ral studies by partners of Jean-Léon with Alzheimer’s disease. In effect, the Thomas, at Yale University, on the epige- decline of the mechanism of neuroge- netic control of embryonic neurogene- nesis during aging could be implicated sis119,120,121 and the function of VEGFR3 in the emergence of neurodegenerative signaling122,123. pathologies such as Alzheimer’s disease.

2. Cortical networks

The cerebral cortex is the structure of identified a process of auto-modula- the brain where sensory information is tion of the principle cortical neurons, processed, stored, and used to generate pyramidal neurons, by a retrograde elaborate behaviors and for cognitive mechanism that affects their own elec- functions. The coordinated activity of a trical activity124. The excitation/inhibi- myriad of different neurons connected tion (E/I) ratio of these neurons must in complex functional networks enables remain constant in time and in intensity the brain to accomplish this. The activity to regulate complex cognitive functions of cortical neurons, brain cells respon- and prevent the appearance of neuro- sible for memory and consciousness, logical and psychiatric diseases. The requires the precise integration of nerve pyramidal neurons can block the E/I impulses that they receive, excitatory or ratio by increasing the intensity of their inhibitory. Dysfunction of these neurons own inhibition by specific interneu- causes neurological and psychiatric rons, small neurons that project locally, disorders, including epilepsy, autism, characterized by the expression of a schizophrenia (see Cognition and molecule called parvalbumin. psychiatric disorders). Understanding These studies reveal the existence of how the cortical neurons integrate the a selective inhibitory mechanism of multitude of signals they receive is the neuronal plasticity by interneurons. first step in the detection of anomalies They also help to better understand the and eventually in the prevention of neuro- regulation of the neuronal circuits that logical diseases. The studies of the team underlie cortical functions. The modu- of Alberto Bacci concern the regulation lation of electrical signals can play a of neuronal microcircuits in the heal- crucial role in cortical activity and the thy brain at the origin of normal corti- treatment and integration of sensory cal function. The researchers recently information.

50 ICM ANNUAL REPORT 2014 3. Locomotor circuits

In the spinal cord, the central pattern sensory neurons are localized at the generator for walking allows one to level of the central canal of the spinal move naturally without having to think. cord and contact the cerebrospinal Nevertheless, when there is a medul- fluid. When they are activated, either lary lesion, new means of reactiva- by a chemical or mechanical stimulus, ting the spinal circuits (circuits of the they send information to other neurons spinal cord) must be found. The team involved in locomotion. This previously of Claire Wyart, Pierre-Luc Bardet, and unknown neuronal pathway, conserved Hugues Pascal Moussellard seeks to among vertebrates, links the internal understand how spinal cord circuits are state of a person, via the cerebrospinal recruited during locomotion, how they fluid, with the central pattern genera- develop, and how they can be stimu- tor for walking. This discovery opens a lated or reactivated when lesioned. new field of investigation on the possibi- In order to study the morphology lities of modulating pharmacologically and the role of genetically identified the motor circuits of the spinal cord in neurons in vivo, this team makes use case of a lesion or a neurodegenerative of the transparency of the zebrafish. In disease. particular, the team studies the role of local sensory information that commu- In collaboration with Fabrizio De Vico nicates with spinal circuits about the Fallani and Mario Chavez of the ARAMIS state of muscle contraction and posture team of Olivier Colliot and Didier during a movement. The group has Dormont, the researchers have deve- characterized a new sensorimotor loop loped a mathematical model to charac- in the spinal cord conserved across terize the connectivity of motor networks vertebrate species125. The implicated in the zebrafish126 (see Modeling).

ICM ANNUAL REPORT 2014 51 BIBLIOGRAPHICAL REFERENCES RESEARCH 1 7 BIBLIOGRAPHICAL REFERENCES

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All publications of ICM researchers are available on the internet site of the Institute icm-institute.org.

ICM ANNUAL REPORT 2014 55 RESEARCH 1 GLOSSARY

Axon: nerve fiber conducting electric signals from the Mutation: modification of genetic information causing a neuron’s cell body towards its target to transmit the genetic disease. signals at synaptic terminals. Myelin: insulating and protective sheath around nerve Basal ganglia: grey matter (composed of neuronal cell fibers that facilitates transmission of signals in the bodies) situated deep in the brain, which intervenes nervous system in particular in the control of movement and voluntary movements through interactions with cortical areas. Neural stem cells or progenitors: cells that can differentiate into neurons or glial cells. Brainstem: part of the brain situated between the brain hemispheres and the spinal cord. It controls vital functions Neuron: nerve cell assuring the transmission of the nerve including swallowing, respiration, cardiac rhythm, and impulse. It is composed of receptive elements called wakefulness, and contains the motor and sensory nuclei dendrites, a cell body that integrates information,and of the head and the neck. an axon that transforms information in the form of an Central nervous system: composed of the brain and the electric signal. spinal cord. Neurotransmitter: chemical substance used by neurons Cerebellum: located behind the brainstem. It is to communicate with each other or another cell in the implicated in the control of balance and the coordination organism, such as a muscle cell of movements. Oligodendrocyte: myelin producing cell. Cerebrospinal fluid: liquid that circulates in the brain. It transmits nutrients to nerve cells and eliminates debris. Oncogene: a gene that favors development of a cancer when expressed. Cortex: the outermost part of the brain, also called grey matter. Part of the information transmitted by the neurons Peripheral nervous system: part of the nervous system arrives and leaves at the level of the cortex. formed by the ganglia and nerves outside the brain and the spinal cord. Its principle function is to transmit Dendrites: Nerve fibers that receive electrical messages information between limbs and organs and the central sent by other neurons to transmit them to the cell body. nervous system. DNA: molecule present in all cells that contains the information needed for the development and the Pharmacologically: based on the use of a medication. functioning of living beings. It is the molecule that Phenotype: the morphological, physiological, and contains genetic information. behavioral characteristics of an individual. Gene: sequence of DNA containing the code for the Spinal: production of one or more proteins (or regulation of concerning the spinal cord. protein expression level). Spinal cord: directly connected to muscles by the nerve Genotype: the collection of genes of an individual. roots then the nerves. It transmits information from the brain to muscles and the viscera. The spinal cord Glial cells: cells that form the environment of the neurons. transmits sensory information from the limbs, the trunk, These include several subtypes. Oligodendrocytes and the viscera to the brain in return. produce myelin, astrocytes have protective and support functions and supply nutrients and oxygen, and microglial Striatum: brain structure situated under the cortex that is cells eliminate dead cells and fight against pathologies. part of the basal ganglia.

Hippocampus: structure of the brain that plays a central Synapse: functional contact zone between two neurons or role in memory. a neuron and another type of cell (muscle cell, sensory Medullar: concerning the spinal cord cell, etc.). Microglial cells: Immune cells responsible for the defense Transcription: first tep s of the process that transforms of the central nervous system. the information encoded in genes into proteins.

56 ICM ANNUAL REPORT 2014

THE IHU-A-ICM

1 Major achievements

2 Major publications 2

The mission of the IHU-A-ICM is to conduct projects of excellence in care, training, and technology transfer in the field of research on the diseases of the nervous system. Its priority is to favor the development of innovative diagnostic and therapeutic products and procedures. The objectives of the IHU-A-ICM, Paris Institute of Translational Neurosciences, are: development of international level research in the field of the diseases of the nervous system (neurology and psychiatry), creation of advanced technical platforms, promotion of research results, research partnerships with industry, training of future professionals in health, health administration and heath industries, improvement of care, and transfer of care from the hospital to the homes of patients.

ICM ANNUAL REPORT 2014 59 THE IHU-A-ICM

EDITORIAL FREDERIC SALAT-BAROUX, PRESIDENT OF THE IHU-A-ICM

Since its creation in February 2012, faith in progress at the service of those the role of the IHU-A-ICM has been to who suffer and their families. understand the function and dysfunction I also want to acknowledge the quality of the nervous system, which is a major of our collaboration with our founding challenge for research. It has benefited members and first of all the ICM. We are to that end from an unprecedented finan- engaged with them in a wonderful collec- cial effort on the part of government that tive adventure. has engaged us and encourages us to advance in response to the confidence I want to acknowledge most of all the placed in our institution. new impetus given to the institute by its Faithful to the spirit of its founders and Director General, Prof. Bertrand Fontaine, its missions, the IHU-A-ICM has conti- with the launching of ever more inno- nued its efforts to favor the emergence vative transversal research programs, of new results and new concepts thanks which will permit the institute to mobi- to an interdisciplinary scientific strategy lize its resources in the service of stra- based on the most innovative techniques tegic scientific orientations. and close to the patients. Constant engagement, innovative spirit, At the end of the institute’s third year of cohesion of the teams, such are the key existence, I want to acknowledge the first words and the principles that, this year very promising results obtained. again, will guide each of us and the IHU-A- ICM as a whole. These results are due first of all to you, your work, and your engagement, your Thank all you again.

60 ICM ANNUAL REPORT 2014 EDITORIAL BERTRAND FONTAINE, DIRECTOR GENERAL OF THE IHU-A-ICM

The IHU-A-ICM unites a critical mass of clini- contribute both to research on neurodege- cians and talented researchers capable of nerative diseases and the improvement major discoveries in a synergistic ensemble of care. and is today able to attract the best inter- The institute has finalized, in the context national researchers. The Paris Institute of a joint action with the ICM, the recruit- of Translational Neuroscience, the IHU-A- ment of a foreign senior researcher, selec- ICM, the fruit of a governmental program ted by the International scientific advisory of investments for the future, celebrates board common to the IHU-A-ICM and its three years of existence. In this year, the ICM. His scientific project is aimed at which will see the first evaluation of our understanding the mechanisms of gene- work by the international jury that selected tic control from cell specification to the us, we are proud to present a very positive molecules implicated in neurodegenera- appraisal and promising results. tive diseases such as Alzheimer’s disease. In matters of care, the IHU-A-ICM has This recruitment confirms the attractive- made spectacular advances with the acti- ness of our Institute, made possible by the vity of the Behavioral Neuropsychiatry IHU program of investments for the future. Unit. Since its opening, 250 patients have Finally, the ICM and IHU announced in been examined, 80% benefitted from June 2015, the launching of the “Big Brain receiving a diagnosis at the end of their Theory” program. This new program will stay, and 77% had a treatment adapted permit the attribution of grants for new to their condition that was different from innovative and interdisciplinary projects in their treatment when they entered the unit. neuroscience for the researchers and clini- The IHU also showed its ability to consti- cians of the Institute. This call for projects tute large cohorts with the recruitment emphasizes originality and risk-taking, of 400 subjects for the INSIGHT study, an and will free the researchers from admi- innovative study on Alzheimer’s disease, nistrative duties by financing completely one of the first studies to follow healthy the projects selected by the international at-risk subjects with great ambitions for scientific advisory board of the IHU-A- understanding the disease, performed in ICM and ICM. partnership with Pfizer. I wish to warmly thank the patients, resear- In 2014, the acquisition of major equipment chers, clinicians, support teams, and our foreseen since the beginning was fina- partners that have made the dreams of lized. The IHU-A-ICM has acquired a mixed the IHU a reality, and also our founders, PET-MRI system thanks to an exceptio- the AP-HP, the UPMC, INSERM, the CNRS, nal fundraising campaign and sponsors the FRA, and the ICM, for their constant in collaboration with two of its founding support. The year 2015 opens with strong members, the APHP and the Foundation achievements and ambitious and crea- for Research on Alzheimer’s disease. It’s tive perspectives to accelerate research the first mixed PET-MRI system for the and the discovery of new treatments for clinic and research on a French site. It will our patients.

ICM ANNUAL REPORT 2014 61 Major achievements THE IHU-A-ICM 2 1 Major achievements

The IHU has assembled a critical mass of examined, 80% of whom received a talented, well-integrated clinicians and diagnosis and 77% a treatment adap- researchers and is capable of attracting ted to their condition that differed from international participants. The IHU fina- the treatment they were receiving when lized negotiations with a senior foreign they entered the unit. Finally, the IHU candidate selected by the International has demonstrated its ability to consti- scientific advisory board. He was tute large cohorts with the recruitment ranked first in an international call for of 343 subjects included in the INSIGHT projects, “New Teams,” with a scienti- study in partnership with Pfizer. fic project aimed at understanding the The Paris Institute of Translational mechanisms of genetic control star- Neuroscience (IHU-A-ICM) has pursued ting with cell specification. The IHU-A- the pilot procedures it established at the ICM acquired a mixed PET-MRI system start of the program. thanks to an exceptional fundraising campaign and patronage in collabo- In 2014, reflection was begun onscienti- ration with the support of two of its fic policy jointly with the Brain and Spine founding members, the AP-HP and Institute (ICM). This analysis consists of the Fondation pour la Recherche sur evaluating the first results of the IHU-A- Alzheimer. It is the first mixed PET-MRI ICM, in order to propose a new joint system for research and the clinic on a and transversal scientific organization French site. In the context of its indus- of the two foundations and to develop trial strategy, the IHU has established new initiatives and ambitious projects. a partnership with a French company, For the first time, a joint meeting of the Medtech, for the acquisition of a ROSA Boards of Directors of the IHU and the robot for neurosurgery. In 2014, the ICM took place in September 2014. IHU finalized the acquisition of major The IHU-A-ICM acquired a mixed equipment planned from the beginning PET-MRI system thanks to sponsorship, of the program. The IHU-A-ICM began in collaboration with the support of two a major reorganization of its platforms of its founding members the AP-HP in order to optimize its fees and offer a and the Fondation pour la Recherche diversity of services for industrial users. sur Alzheimer. This equipment will be The IHU-A-ICM has recruited 18 staff functional in the fall of 2015. The ability members for the platforms, mostly with to acquire perfectly recorded images permanent contracts. In terms of care, in two modalities in a single imaging the IHU-A-ICM has also made spec- session while maximizing the quantita- tacular advances since the opening of tive and clinical information is a unique the Behavioral Neuropsychiatry Unit. contribution to research on neurological Since it opened, 250 patients have been diseases and the constitution of cohorts

62 ICM ANNUAL REPORT 2014 in the framework of the IHU-A-ICM. It is The team of the Alzheimer Project the first mixed PET-MRI machine for the has continued its efforts to develop clinic (used by the APHP) and research the INSIGHT cohort in collaboration (used by the IHU-A-ICM) on a hospi- with Pfizer. The objective of including tal site. The informatics connections in the INSIGHT cohort 90 subjects over required for research were established 70 years of age with PET AV45-positive between the site of image acquisition amyloid was reached in 2014. This and the research laboratories. required the successful inclusion of a total of 343 subjects in the study. The In 2014, the acquisition of major multimodal database is being deve- equipment planned by the program was loped and the first analyses have begun. finalized. The IHU-A-ICM in conjunction with the ICM began a major reorganiza- The teams of the Multiple Sclerosis tion in order to optimize the functioning Project demonstrated the inhibi- of the technical platforms, establish an tory role of endothelin1 in remyelina- optimal price scale, and standardize all tion and showed, in collaboration with procedures. the Children’s Hospital, Washington, D.C., that this molecule constitutes a Finally, the IHU-A-ICM, as the UPMC new pharmacological target to initiate winner of the European public-private remyelination (publication in the presti- program KIC (Knowledge and innova- gious journal Neuron). tion communities), is a partner in the The Motivation Project chose, in neuroscience and innovation program conformity with the IHU concept, to KIC-Innolife (Healthy aging) The IHU-A- create long-lasting structures that ICM was strongly involved in this appli- could not have been developed with cation through the action of its Director just the usual financing: the Behavioral General, a member of the pilot commit- Neuropsychiatry Unit (UNPC) in the tee of the French sector. He developed clinical domain, the PRISME platform partnerships with the AP-HP and Air for the study of human behavior in the Liquide, and was one of the French research domain, and diverse academic representatives in the “education” and and societal initiatives in the educatio- “brain” groups during the development nal domain. Since the opening of the of the project. UNPC in November 2013, 250 patients have been examined. The diagnoses The team of the Parkinson Project conti- most frequently made are degenerative nued including patients in the ICEBERG diseases and severe depressive disor- cohort at the center of the clinical ders that mimic dementia; 80% of the project of the IHU: study of factors patients had a new or confirmed diag- predicting the conversion to and the nosis after their stay in the unit and 77% progression of Parkinson disease. The had a treatment adapted to their situa- rhythm of recruitments is as expected. tion that differed from their treatment The team also identified a viral peptide when they entered the unit. that is neuroprotective in models of Parkinsonian diseases, this led to a Among the major achievements of the publication in Nature Communications Epilepsy Project, the teams pursued and and a patent. further developed a new translational

ICM ANNUAL REPORT 2014 63 Major achievements THE IHU-A-ICM 2

project in patients and in a rodent model one-day hospitalisations) participating aimed at exploring the excitability of in 62 studies: 43 studies in the CIC and cortical neurons and cortical responses 19 in the CET. Privileged partnerships to sensory stimulation during isoelec- with the private sector are continuing or tric comas. The team also identified a de being initiated. novo mutation in the HCN1 ion channel The Care Project has continued its gene in children with fever-sensitive efforts with the recruitment of a coordi- epileptic encephalopathies. The intrin- nator to create, with ARS Ile-de-France, sic properties of the mutated channels a pole “Handicap Ile-de-France.” Three were studied by the electrophysiology working groups were formed and have platform of the IHU leading to a publica- begun their activity, which should be tion in Nature Genetics. finished in July 2015. The Bioinformatics/Biostatistics Project The actions of the Educational Project began in 2013 with the recruitment of are described among the socioecono- its scientific coordinator. This platform mic impacts (actions undertaken for develops methods dedicated to the sharing knowledge, teaching). analysis of multimodal data (RGCCA): genetic, genomic, transcriptomic, The plan of action of the Strategy Project epigenomic, metabolomic, clinical, was pursued during 2014. The IHU fina- and neuroimaging. The team created a lized negotiations with Dr. Bassem pole “Databases and Datawarehouse” Hassan (VIB, Leuven, Belgium), who and recruited its director in June 2014. was ranked first in the international call The team also developed a complete for projects “New Teams.” The scienti- pipeline (treatment, analysis, interpre- fic project of this team is to understand tation, visualization) of data concerning the mechanisms underlying the genetic genetic variants (gene panel, whole- control of cell specification and to trans- exome sequencing), in relation with the pose these basic approaches to disease Genotyping-Sequencing platform. The models. What is new is the senior status project has been completed and has led of the candidate, until now the Institute to the existence of platforms with an has only attracted junior researchers. associated management unit and the The IHU also launched calls for “Clinic development of technological research. and Care” projects and structural The members of the Clinical Research projects in 2013. The first results of Project have successfully continued this strategy can be appreciated by the the activities of the Clinical research success of two PHRIP projects concer- platform dedicated to neuroscience. ning care. As for internal collaborative In 2014, the CIC and CET received projects, the IHU notably financed a 2904 patients (consultations or project aimed at understanding the role

64 ICM ANNUAL REPORT 2014 of the CIC, a gene frequently mutated in neurophysiology on small animals. oligodendrogliomas, in the development The platform has developed methods of oligodendrocytes and in the genesis for exploring the central and periphe- of these tumors. Characterization of the ral nervous system (electroneuromyo- function of CIC is underway. gram, electromyogram, somatosensory We also wish to describe the advance- evoked potentials), which have led to ment of the transversal projects that the development of five projects. In have reached maturity: association with the Epilepsy project, this platform also offers the possibility The Imaging Project has enabled of long-duration video electroencepha- the development of the imaging silo lograms. The project is now completed platforms in the framework of the IHU and has led to the existence of platforms in association with the ICM. These with an associated management unit platforms are now completely opera- and the development of technological tional with an associated management research. unit and are developing technological research in the following domains: The Cell Culture Project is now comple- multimodal imaging, gait analysis, ted and has led to the creation of imaging in primates, integrated MEG/ platforms with an associated manage- EEG electrophysiology. During 2014, ment unit and the development of tech- the imaging silo organized a series nical research. Three platforms have of courses that were a success. The developed services (fee-based) and program will be repeated in 2015. These technologies: cell culture and scree- platforms also led to the publication of ning, culture of iPS cells, electrophysio- many articles reflecting the efficacy of logy, and screening. The technical offer the translational research program of has now been increased with the instal- the IHU. lation of a second electrophysiology rig Among the major achievements of the for extracellular recordings of electrical Animal Model Project in 2014 was the field potentials on brain slices (in vitro) installation of a platform for in vivo or in the zebrafish(in vivo).

ICM ANNUAL REPORT 2014 65 MAJOR PUBLICATIONS THE IHU-A-ICM 2 2 MAJOR PUBLICATIONS

1. Szelechowski et al. A viral peptide that targets mitochon- 7. Laouchedi M, Galanaud D, Delmaire C, Fernandez- dria protects against neuronal degeneration in models Vidal S, Messé A, Mesmoudi S, Oulebsir Boumghar F, of Parkinson’s disease. Nature Communication 2014. Pélégrini-Issac M, Puybasset L, Benali H, Perlbarg V Deafferentation in thalamic and pontine areas in severe 2. O’Bryant SE et al. Guidelines for the standardization of traumatic brain injury. J Neuroradiol. 2014 preanalytic variables for blood-based biomarker studies in Alzheimer’s disease research. . Alzheimers Dement. 2014 8. Mesci et al. System xC- is a mediator of microglial function and its deletion slows symptoms in amyotrophic late- 3. Hammond et al. Astrocyte-derived endothelin-1 inhi- ral sclerosis mice. Brain 2014 bits remyelination through notch activation. Neuron, 2014. 9. Esteves T, (2014). Loss of association of REEP2 to 4. Lagarde et al. Why do patients with neurodegenerative membranes leads to hereditary spastic paraplegia. Am frontal syndrome fail to answer the following question: “In J Hum Genet 94:268-277. what way are an orange and a banana alike?” Brain, 2014. 10 Boxer AL et al. Davunetide in patients with progres- 5. Nava C et al. De novo mutations in HCN1 cause early sive supranuclear palsy: a randomised, double-blind, infantile epileptic encephalopathy. Nat Genet. 46(6):640- placebo-controlled phase 2/3 trial. Lancet Neurol. 2014. 5, 2014. 6. El Mendili MM, Cohen-Adad J, Pelegrini-Issac M, Rossignol S, Morizot-Koutlidis R, Marchand-Pauvert V, Iglesias C, Sangari S, Katz R, Lehericy S, Benali H, Pradat PF. Multi-parametric spinal cord MRI as potential progression marker in amyotrophic lateral sclerosis. PLoS One. 2014 Apr 22;9(4):e95516.

INSTITUTION DU CERVEAU ET DE LA MOELLE EPINIERE ÉQUIVALENCES QUADRI ICM_09_2742_LogoFr_Quad 26/08/2009 MAGENTA 70% JAUNE 100% 24, rue Salomon de Rothschild - 92288 Suresnes - FRANCE Tél. : +33 (0)1 57 32 87 00 / Fax : +33 (0)1 57 32 87 87 Web : www.carrenoir.com CYAN 100% MAGENTA 70% NOIR 60% Ce fichier est un document d’exécution créé sur Illustrator version 10.

66 ICM ANNUAL REPORT 2014

TECHNICAL PLATFORMS

1 Molecular exploration

2 Cellular exploration

3 Cellular imaging 4 Functional exploration 3 5 Preclinical functional exploration - phenoparc

6 Bioinformatics and biostatistics – iconics

7 Biological resource center

The quality of scientific discoveries depends on the performance of the technical platforms on which the discoveries are performed. Revolutionary in its conception, innovative in its organization, the ICM is also unique because of its advanced technical equipment.

ICM ANNUAL REPORT 2014 69 MOLECULAR EXPLORATION TECHNICAL PL ATFORMS 3 1 MOLECULAR EXPLORATION

The molecular exploration silo consists gene transfer so that researchers can of two platforms: iGenSeq and iVector. perform experiments using genetic mani- The role of the first, iGenSeq, is dedi- pulations in vitro (outside the organism) cated to sequencing and genotyping the or in vivo (after injection in the organism genome, i.e. reading the long molecu- like a vaccine). These tools are derived les of DNA that form chromosomes. The notably from innocuous modified viruses, aim is to analyze the genome and detect converted into gene transporters. This type possible mutations and associations of technology is the basis of gene therapy, between these mutations and neuro- therapies that act on genes, which ICM logical diseases. The second platform, researchers hope to use to “repair” the iVector, constructs molecular tools for abnormal DNA of patients.

1- iGenSeq – G enotyping and sequencing platform YANNICK MARIE AND GIOVANNI STEVANIN

iGenSeq offers tools and services for the its feasibility and optimize its design. analysis of the genome to academic and This platform offers researchers high- industrial researchers. More specifi- throughput sequencing and PCR accom- cally, the services include real-time PCR, panied by biostatistics services. iGenSeq sequencing, as well as the purification is part of the network of platforms of the and analysis of nucleic acids. Each project ICM , including vectorology, histology, submitted to the platform is discussed microscopy, cell culture, etc. that facili- with the researcher in order to evaluate tates translational research.

ACTIVITIES

• Real-time PCR: with SybrGreen tech- (DNA and RNA): high-throughput with nology or specific probes, quantifica- the NextSeq Illumina system for EXOLE tion of RNA, digital PCR, HRM applications RNAseq and MethylSeq

• Sequencing: medium-throughput with • Genotyping GS junior and Miseq Illumina systems, including multiplex amplicon (Fluidigm • Purification and analysis of PCR products: ACCESS ARRAY), long-range and ultra- PCR or purification of sequences and deep sequencing applications and Capture quantitative analyses of DNA and RNA

70 ICM ANNUAL REPORT 2014 PUBLICATIONS

Coutelier M et al. GRID2 mutations span from congeni- Méneret A et al. Congenital mirror movements: mutatio- tal to mild adult onset cerebellar ataxia. Neurology 2015 nal analysis of RAD51 and DCC in 26 cases. Neurology. (advance online April 3rd). 2014 Jun 3;82(22):1999-2002. Hopfner F* et al. The impact of rare variants in FUS in essen- Gillet E1 et al. TP53 and p53 statuses and their clinical tial tremor. Mov Disord 2015 (advance online January 28). impact in diffuse low grade gliomas. J Neurooncol. 2014 Lossos A* et al. Fe/S Protein Assembly Gene IBA57 May;118(1):131-9. Mutation Causes Hereditary Spastic Paraplegia. Neurology Picard F et al. DEPDC5 mutations in families presenting 2015, 84:659-667. as autosomal dominant nocturnal frontal lobe epilepsy. Baulac S1 et al. Familial focal epilepsy with focal cortical Neurology. 2014 Jun 10;82(23):2101-6. dysplasia due to DEPDC5 mutations. Ann Neurol. 2015 Apr;77(4):675-83. Esteves T et al. Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. Am J Hum Millecamps S et al. Genetic analysis of matrin 3 gene in Genet. 2014 Feb 6;94(2):268-77. French amyotrophic lateral sclerosis patients and frontotemporal lobar degeneration with amyotrophic lateral scle- Boillot M et al. Glutamatergic neuron-targeted loss of LGI1 rosis patients. Neurobiol Aging. 2014 Dec;35(12):2882.e13-5. epilepsy gene results in seizures. Brain. 2014 Nov;137(Pt Nava C et al. De novo mutations in HCN1 cause early 11):2984-96. infantile epileptic encephalopathy. Nat Genet. 2014 Jun;46(6):640-5.

2 - iVector – VECTOROLOG Y PLATFORM PHILIPPE RAVASSARD AND ANDRE SOBCZYK

The vectorology platform (iVector) produces There are different scales of production, a large number of lots of lentiviral vectors and high-titer viruses (a mean of 109 func- every year. These viral vectors are the tools tional viral particles/mL) are delivered of choice for gene transfer in applications after purification. The platform team, in in vitro and in vivo for basic research, close collaboration with the Biotechnology cellular engineering, gene therapy, cell and Biotherapy team, proposes a wide therapy, immunotherapy, and vaccines. variety of empty lentiviral vectors ready The platform’s BSL2 and BSL3 confine- to accept any gene of interest. These two ment laboratories satisfy all demands teams ensure the continual improvement for virus production. iVector constructs and evolution of these vectors. iVector is recombinant viruses, which form viral integrated in the network of ICM platforms particles. (genotyping, histology, microscopy, cell culture, etc.).

ICM ANNUAL REPORT 2014 71 MOLECULAR EXPLORATION TECHNICAL PL ATFORMS 3

ACTIVITIES

• Design and construction of viral and • Quality control: determine of the titer of non-viral vectors. functional viral vectors (FACS, qPCR), • Maxi and Giga preparations, ampli- measure the concentration of physical fication/purification of plasmid DNA viral particles (Elisa p24) (endotoxin-free). • Technical and regulatory advice for the • Production of recombinant Lv (3rd gene- design, production, and use of viral ration “ΔU3” or “SIN”) and Rv (retrovi- vectors. ral) vectors. • Development of new viral tools (CAV-2 • A variety of control lentiviral vectors and rAAV) with serotypes specific for (GFP, miRneg, etc.) are available. research in neurobiology. • Development of transduced cell lines and mini-banking (after feasibility analysis in the laboratory).

PUBLICATIONS

Sepulveda-Diaz JE et al. HS3ST2 expression is critical Morán I et al.Human beta cell transcriptome analysis for the abnormal phosphorylation of tau in Alzheimer’s uncovers lncRNAs that are tissue-specific, dynamically disease-related tau pathology. Brain 138, 1339–1354. regulated, and abnormally expressed in type 2 diabetes. Brain. 2015 May;138(Pt 5):1339-54. Cell Metab. 2012 Oct 3;16(4):435-48. Gleize V et al. CIC inactivating mutations identify aggres- Courtney M et al.The inactivation of Arx in pancreatic alpha- sive subset of 1p19q codeleted gliomas. Ann Neurol. Ann cells triggers their neogenesis and conversion into functio- Neurol. 2015 May 27. nal beta-like cells. PLoS Genet. 2013 Oct;9(10):e1003934. Ingallinesi M et al. Local inactivation of Gpr88 in the Al-Hasani et al. Adult duct-lining cells can reprogram nucleus accumbens attenuates behavioral deficits elicited into beta-like cells able to counter repeated cycles of toxi- by the neonatal administration of phencyclidine in rats. n-induced diabetes. Dev Cell. 2013 Jul 15;26(1):86-100. Mol Psychiatry. 2014 Aug 26. Tepavˇcevi´c V et al. Early netrin-1 expression impairs central nervous system remyelination. Ann Neurol. 2014 Aug;76(2):252-68.

72 ICM ANNUAL REPORT 2014 2 CELLULAR EXPLORATION

ICM researchers work on different scales the axons of certain neurons, accelera- from molecules such as DNA and proteins ting propagation of the nerve impulse. to the organism, as well as the cell, which Research in the ICM requires the availa- is midway between these two extremes. In bility of easily manipulated cell cultures the brain and its continuation, the spinal to reproduce the mechanisms of nervous cord, several types of cells coexist: system pathologies in a simplified manner. • Neurons are the active element of These studies require recording the acti- nervous tissue and play a major role vity of neuronal cells in order to evaluate in the transmission of information. This possible anomalies in the transmission involves successive electrical and chemi- of the electrical signal, manipulation of cal events. Neurons form an incredibly stem cells to produce authentic nerve complex and dense network. Each neuron cells or glia, and also analysis of patho- is composed of a cell body, which inclu- logical cellular dysfunctions by quanti- des the nucleus that contains the DNA, tative fluorescent microscopy. Recently, an axon that transmits information, and it has become possible to perform this dendrites which receive information. type of analysis on living cells in the ICM thanks to automated microscopes. • Glial cells, more numerous than neurons, have specialized functions. Several cell Histological techniques on tissue sections types can be distinguished: enable evaluation of the integrity of popula- tions of neurons and glial cells in different – Microglial cells that act as sentinels and regions of the brain in order to understand preserve the integrity of neurons faced the function or dysfunction of the brain with different types of attacks. as a whole. These techniques need prior – Astrocytes that have support, protec- labeling with antibodies or specific dyes tive, and nutritional functions. to be effective. – Oligodendrocytes that produce the All these activities are possible thanks to myelin sheath, an envelope that insulates four cellular exploration platforms.

ICM ANNUAL REPORT 2014 73 CELLULAR EXPLORATION TECHNICAL PL ATFORMS 3

1 - CELIS – ADVANCED CELL CULTURE E QUIPMENT PATRICK-PIERRE MICHEL AND LAETITIA STREHL

This platform offers a large range of Other activities include the production cellular models as well as advanced and characterization of pluripotent stem technologies to academic and industrial cells (iPS) and electrophysiological recor- researchers who: dings in cultured cells or brain slices. 1 – wish to perform experiments on patho- This platform is part of the network of logies of the brain and the spinal cord ICM platforms (sequencing, vectorology, histology, microscopy, etc.) and is 2 – wish to screen small molecules to supported by the IHU-ICM. discover promising treatments for these pathologies

ACTIVITIES

• Study pathologies of the brain, spinal • Real-time measurements of cell cord, and skeletal muscle on cell cultu- proliferation res or tissue sections. • Electrophysiological characterization • Screen for treatments for neuronal or of ion channel dysfunction glial pathologies, including brain tumors • Conventional ELISA and immunological • Automated cell culture assays by electrochemiluminescence. • Molecular and cellular pharmacology • Flow cytometry • Conventional or automated fluorescence imaging, infrared fluorescence imaging

74 ICM ANNUAL REPORT 2014 PUBLICATIONS

Bertolin G et al. Parkin maintains mitochondrial levels of Esteves T et al. Loss of association of REEP2 to membra- the protective Parkinson’s disease-related enzyme 17-ß nes leads to hereditary spastic paraplegia. Am J Hum hydroxysteroid dehydrogenase type 10. Cell Death Differ. Genet 94:268-277. Freeman SA et al. Acceleration of conduction velocity Marquer C et al. Increasing membrane cholesterol of linked to clustering of nodal components precedes myeli- neurons in culture recapitulates Alzheimer’s disease nation. Proc Natl Acad Sci U S A. 112:E321-8. early phenotypes. Mol Neurodegener. 9:60. Guerreiro S et al. The sleep-modulating Peptide orexin-B Tepavˇcevi´c V et al. Early netrin-1 expression impairs central protects midbrain dopamine neurons from degeneration, nervous system remyelination. Ann Neurol. 76:252-68. alone or in cooperation with nicotine. Mol Pharmacol. 87:525-32.

2 - CELIS - E-PH YS – ELEC TROPHYSIOLOGY PLATFORM CARINE DALLE AND PATRICK-PIERRE MICHEL

CELIS-E-PHYS offers high level services platform is thus important for numerous to academic and industrial researchers research projects ranging from the func- needing electrophysiological data in vitro tional characterization of channelopathies and in vivo (zebrafish). This type of data to that of neurons derived from human is essential for all neuroscience studies induced pluripotent stem cells (iPSC). concerning the biophysical properties CELIS-PHYS is part of the network of ICM of ion channels, the functional charac- platforms (sequencing, vectorology, cell terization of all types of cells, and the culture, iPS…) that facilitate translatio- study of synaptic and electrical activity nal research. CELIS-PHYS is supported in the nervous system in general. The by the IHU-A-ICM.

ACTIVITIES

• Generation of electrophysiological data • Preliminary studies to evaluate the (including experimental design, data feasibility of research projects acquisition, analysis, and interpretation) • Specialized advice on electrophysiology • Electrophysiology rigs with technical • Training of students and engineers in support electrophysiological techniques

PUBLICATIONS

Nava C et al. De novo mutations of the hyperpolarization-ac- responsible for early infantile epileptic encephalopathy. tivated cyclic nucleotide-gated channel 1 gene (HCN1) are Nature Genetics, 2014 Jun;46(6):640-5

ICM ANNUAL REPORT 2014 75 CELLULAR EXPLORATION TECHNICAL PL ATFORMS 3

3 - CELIS – IPS – PLATFORM FOR THE PRODUCTION OF HUMAN INDUCED PLURIPOTENT STEM CELLS DELPHINE BOHL, PATRICK-PIERRE MICHEL AND SOPHIE DUFFAURE

Human induced pluripotent stem cells, The objectives of the platform are to provide iPSc, are produced in order model dege- a service to generate human induced nerative diseases of the brain and spinal pluripotent stem cells (iPS) as well as to cord in a culture dish. The aim is to study offer training and advice for cell culture. the molecular and cellular mechanisms This activity is part of the cell culture at the origin of these diseases and deve- platform of the ICM and is supported by lop a screening system to identify mole- the IHU-A-ICM. cules of therapeutic interest.

ACTIVITIES

• Services • Scientific and technical advice for users Reprogramming of human somatic Optimization and improvement of protocols cells into iPSc • Development Molecular and functional characteri- Generation and characterization of neural zation of iPSc stem cells derived from iPSc Culture and storage of iPSc Genetic modification of iPSc • Provide equipment for independent users

76 ICM ANNUAL REPORT 2014 4 - HISTOMICS – HISTOLOG Y PLATFORM (study of normal and pathological tissues) BENOIT DELATOUR AND ANNICK PRIGENT

Histomics is a technical support center technical and scientific services, trains open to ICM researchers and academic users in histological methods, and also and industrial partners. The center rents works on independent projects. Histomics equipment or provides services and uses is part of the network of platforms of the standardized protocols and advanced mate- ICM (genotyping-sequencing, vectoro- rial (ultramicrotomes, cryostats, freezing logy, cellular exploration, etc.) that faci- microtomes, etc.) for treating histologi- litate translational research. cal samples. The platform team offers

ACTIVITIES

• Infrastructure rental: equipment and • Technical advice, help with developing reagents are available for indepen- new protocols dent users • Histological services: paraffin inclu- • Training: histological techniques (cutting, sion, sectioning, histo- or immunohis- staining immuno- or histochemistry) tochemical staining

PUBLICATIONS

Epelbaum S et al. Acute amnestic encephalopathy in amyloid-ß oligomer-injected mice is due to their widespread diffusion in vivo. Neurobiol Aging. 2015 Jun;36(6):2043-52.

ICM ANNUAL REPORT 2014 77 CELLULAR IMAGING TECHNICAL PL ATFORMS 3 3 CELLULAR IMAGING

A group of ICM platforms is entirely dedicated fluorescence and phosphorescence. This to cell and tissue imaging. These platforms includes classical fluorescence microscopy, provide access to the most recent techni- confocal microscopy, two-photon micros- ques thanks to advanced imaging material: copy, and spinning disk confocal microscopy - Classical microscopy: observation of - Transmission electronic microscopy to microscopic samples by incident illumination observe different cellular compartments - Video microscopy to follow cellular move- (organelles, viruses, crystals, molecules) ment in real time at high resolution - Fluorescence microscopy: observation of molecules, cells, or tissue sections by

1 - IMAGE AC QUISITION ANNE BARON-VAN EVERCOOREN AND CORINNE BACHELIN

iGenSeq offers tools and services to acade- and to optimize its design. This platform mic researchers and industrial partners also provides techniques such as high for analyzing the genome. These services speed real-time PCR and sequencing with include real-time PCR and sequencing, biostatistics services. iGenSeq is part of as well as purification and nucleic acid the network of ICM platforms (vectoro- analysis. Each project submitted to the logy, histology, microscopy, cell culture, platform is discussed with the resear- etc.) that facilitates translational research. chers in order to evaluate its feasibility

2 - OPTOGENETIC TWO-PHOTON MICROSCOP Y CLAIRE WYART

3 - PICPS – PITIE-SALPETRIERE CELL IMAGING PLATFORM ANNE BARON-VAN EVERCOOREN AND CLAUDE-MARIE BACHELET

78 ICM ANNUAL REPORT 2014 4 FUNCTIONAL EXPLORATION

The functional exploration platforms • Research in the cognitive sciences: permits carrying out of experiments on understand brain function and study living organisms (in vivo) in a non-invasive the neural bases of thought, behavior, manner that respects the integrity of the and aging. subject. These platforms are particularly • Research on signal and image analy- adapted to human subjects – patients or sis: development of new methods for healthy volunteers. processing brain imaging data These platforms support three main The functional exploration platforms research axes: offer techniques for recording brain acti- • Clinical research: study of the evolution vity and high resolution imaging such as of the major pathologies of the nervous magnetic resonance imagery (MRI), elec- system and development of treatments troencephalography (EEG), and magne- toencephalography (MEG).

1 - CENIR-human MRI – NEUROIMAGING FOR RESEARCH STEPHANE LEHERICY AND ERIC BARDINET

The CENIR (Neuroimaging research center) has complementary skills (neuroimaging, is the main MRI platform for imaging in vivo. neuroscience, image analysis, stimula- With expertise in the fields of neurodege- tion, physics of MRI, data analysis) and nerative diseases, cognitive neuroscience, helps carry out research protocols (more and image analysis, the CENIR proposes than 80 projects in 2014) thanks to the high quality imaging tools for research imaging equipment. The use of 3T MRI on the brain and spinal cord to academic and MRI-compatible EEG creates a perfect and industrial researchers. The CENIR environment for carrying out neuroima- human MRI team, composed of 15 people, ging projects.

ICM ANNUAL REPORT 2014 79 FUNCTIONAL EXPLORATION TECHNICAL PL ATFORMS 3

ACTIVITIES

• Clinical research: integrated studies of • Image processing: development of the physiopathology of neurological and methods for processing data as well psychiatric diseases, including clinical as tools for structural and functional and therapeutic care. The protocols imaging concern all of the major pathologies of • Support for researchers: development the nervous system: neurodegenera- of stimulation programs, acquisition tive diseases, white matter pathologies, protocols, and help with different stages epilepsy, motor disorders, psychiatry, of data analysis brain plasticity, and functional recovery. • Cognitive neuroscience: brain function, neural bases of cognition and behavior, aging

PUBLICATIONS

Tabrizi SJ et al. Predictors of phenotypic progression and Worbe Y et al. Reinforcement learning and Gilles de la disease onset in premanifest and early-stage Huntington’s Tourette syndrome: dissociation of clinical phenotypes disease in the TRACK-HD study: analysis of 36-month and pharmacological treatments. Arch Gen Psychiatry. observational data. Lancet Neurol. 2013 Jul;12(7):637-49 2011 Dec;68(12):1257-66 Lebreton M et al. A critical role for the hippocampus Charron S et al. Divided representation of concur- rent in the valuation of imagined outcomes. PLoS Biol. 2013 goals in the human frontal lobes. Science. 2010 Apr Oct;11(10):e1001684 16;328(5976):360-3 Meyniel F et al. Neurocomputational account of how the human brain decides when to have a break. Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2641-6

80 ICM ANNUAL REPORT 2014 2 - CENIR-MEG/EEG – MEG AND EEG PLATFORM FOR RESEARCH PROJECTS IN NEUROSCIENCE NATHALIE GEORGE AND DENIS SCHWARTZ

The CENIR-MEG/EEG platform is part equipment, the CENIR-MEG/EEG team of the Neuroimaging research center helps its academic and industrial part- (CENIR). The platform is dedicated to the ners design and perform their clinical development of non-invasive methods or basic research projects and analyze that allow visualization of brain activity results. CENIR-MEG/EEG is part of the under normal or pathological conditions network of ICM platforms (MRI, PANAM, with a temporal resolution on the order PRISME…) that facilitate translational of a millisecond. Thanks to its advanced research.

ACTIVITIES

• Clinical and basic research on the normal recordings, peripheral neurophysiolo- and pathological brain gical recordings) • Development of methods for the inte- • Creation of software for data processing, grated analysis of electrophysiological statistical analysis, and visualization data at several levels (EEG, MEG, deep

PUBLICATIONS

Huijgen J et al. Amygdala processing of social cues Dumas J et al. Revisiting mu suppression in autism spec- from faces: an intracerebral EEG study. Soc Cogn Affect trum disorder. Brain Research – 2014 - 108-119 10.1016/j. Neurosci. 2015 May 11. pii: nsv048. [Epub ahead of print] brainres.2014.08.035 Koenig et al. Averaging auditory evoked magnetoencepha- Aissani C et al. Beta, but Not Gamma, Band Oscillations lographic and electroencephalographic responses: a criti- Index Visual Form-Motion Integration. PLoS ONE 9(4): cal discussion. European Journal of Neuroscience, 2015 e95541. - Vol. 41, pp. 631–640, 2015. Park HD et al. Spontaneous fluctuations in neural Ulloa JL et al. Sustained neural activity to gaze and emotion responses to heartbeats predict visual detection, Nature perception in dynamic social scenes. Social Cognitive And Neuroscience 17, 612–618. Affective NeurosciencE – 2014 – 9 – 3:350- 357 - 10.1093/ Morel S et al. ERP evidence for an early emotional bias scan/nss141 towards happy faces in trait anxiety, Biological Psychology, Sieluzycki J et al. Maximum-likelihood estimation of 99, 183-192. channel-dependent trial-to-trial variability of auditory Meyniel et al. Better get back to work: a role for motor evoked brain responses in MEG - Biomedical Engineering beta desynchronization in incentive motivation. J Neurosci. online 2014 10.1186/1475-925X-13-75 34(1): 1-9.

ICM ANNUAL REPORT 2014 81 FUNCTIONAL EXPLORATION TECHNICAL PL ATFORMS 3

3 - PLATFORM FOR THE EXPLORATION OF HUMAN BEHAVIOR MATHIAS PESSIGLIONE, PHILIPPE FOSSATI, AND PIERRE LEBOUCHER

PRISME is the ICM platform dedicated are not limited to the laboratory context. to the functional exploration of human The aim is to 1) test a large number of behavior. It is composed of two entities: subjects so that they will be as represen- 1 – PRISME-Virtual Reality has recognized tative as possible of the general popu- expertise in the modeling of virtual worlds. lation, 2) set up environments close to This platform develops and adapts new those found in everyday life, and 3) use virtual reality paradigms for behavioral wireless recording systems so that the and cognitive neuroscience. The platform patients are free to move. also develops new equipment and thera- Academic and industrial partners can use peutic protocols adapted to neuropsychia- the equipment and are assisted by the tric diseases. team to develop appropriate protocols. 2 – PRISME-Real Life is intended for the PRISME is part of the network of ICM study of cognitive functions, human beha- platforms (MRI, MEG/EEG, TMS…) that vior, and social interactions in ecological facilitate translational research. conditions, so that the results obtained

ACTIVITIES

PRISME-Virtual Reality PRISME-Real Life • Cognitive reeducation program, inclu- • Test cognitive functions ding web-therapy and therapy by virtual • Evaluate competency for sports reality • Study social interactions • Walking and fear of falling, spatial cognition, and interpersonal space • Automatic analysis of behavior • Social interactions: embodied conver- • Freely moving subjects sational agent • Multimodal recordings • Virtual reality: environments and crea- • Brain stimulation tion of avatars

82 ICM ANNUAL REPORT 2014 4 - CENIR-STIM – STEREOTAXIS PLATFORM (TECHNI QUES, IMAGES, MODELS) JEROME YELNIK, CARINE KARACHI, AND SARA FERNANDEZ VIDAL

STIM is part of the Neuroimaging research The platform is involved in several deep center (CENIR). STIM offers support for brain stimulation (DBS) protocols in the analysis and development of compu- collaboration with other research insti- ter programs for treating stereotactic tutes and industry. Other departments imaging data (used, for deep brain stimu- of the Pitié-Salpêtrière Hospital, inclu- lation, pharmaco-resistent epilepsies, and ding Neuroradiology, Neurosurgery, and radiosurgery). It offers clinicians tools Neurology contribute their expertise to the for the stereotactic localization of deep platform. The network of ICM platforms brain structures. The YeB Atlas, deve- (more than 20) facilitates translational loped by Jérôme Yelnik and Eric Bardinet, research. is a powerful support for data analysis.

ACTIVITIES

• Pre-surgical determination of targets • Expertise: for DBS Evaluation of new MRI sequences by resear- • Pre- and post-operative localization of chers and engineers in order to discover DBS electrodes previously unknown brain regions • Optimization of MRI sequences for DBS Close collaboration between researchers protocols and clinicians • Data analysis with the YeB Atlas • Development of computer programs for DBS and epilepsy

5 - CENIR-PANAM – PH YSIOLOGY AND MOVEMENT Analysis PLATFORM JEAN-CHARLES LAMY AND MARIE-LAURE WELTER

The PANAM platform is part of the In addition, the platform develops new Neuroimaging research center (CENIR). non-invasive techniques based on trans- Its mission is twofold: cranial magnetic stimulation (TMS) that 1 – Clinical and therapeutic research with safely alters electrical activity through non-invasive brain stimulation on neuro- the skull with strong temporary magnetic logical and psychiatric disorders fields and coupled recordings LFP/EEG (LFP=Local field Potential). The platform 2 – The study of movement, gait, and is part of the network of ICM platforms balance in patients with neurological (preclinical models, neuroimagery, MEG/ disorders. EEG, deep brain stimulation, etc.) that facilitate translational research.

This Platform received support from the RATP Foundation.

ICM ANNUAL REPORT 2014 83 FUNCTIONAL EXPLORATION TECHNICAL PL ATFORMS 3

ACTIVITIES

• Electrophysiological studies (TMS, EMG, • Development of non-invasive stimulation EEG, LFP…) of the cerebellum (TMS, tDCS, tACS…) • Clinical research and experimental thera- • Development of coupled recordings:TMS/ peutics using non-invasive stimulation MRI, TMS/EEG, and LFP/EEG • Mapping of cortical organization/disorga- • Evaluation of therapeutic treatments nization in neuropsychiatric pathologies on patients with motor and behavioral (Parkinson’s disease, ALS, essential disorders, including gait and balance tremor, congenital mirror movements, problems primary orthostatic tremor, dystonia, • Development of intracerebral recor- autism…) dings coupled with biomechanical/ • Effects of “virtual” brain lesions on cinematic/EEG parameters, including cognitive and motor tasks when walking • Development of experimental therapeutics for neuropsychiatric disorders with high and low frequency rTMS and tDCS,

PUBLICATIONS

Quentin R et al. Cereb Cortex. Visual Contrast Sensitivity Kishore A, Popa T, James P, Yahia-Cherif L, Backer F, Improvement by Right Frontal High-Beta Activity Is Varughese Chacko L, Govind P, Pradeep S, Meunier S. Mediated by Contrast Gain Mechanisms and Influenced Age-related decline in the responsiveness of motor cortex by Fronto-Parietal White Matter Microstructure. J Neurol. to plastic forces reverses with levodopa or cerebellar 2015 Jun;262(6):1515-25. stimulation. Neurobiol Aging. 2014 Nov;35(11):2541-51. Welter ML et al. PPNa-DBS for gait and balance disor- Kishore A et al. Cerebellar sensory processing alte - ders in Parkinson’s disease: a double-blind, randomised rations impact motor cortical plasticity in Parkinson’s study. J Neurol. 2015, in press disease: clues from dyskinetic patients. Cereb Cortex. 2014 Aug;24(8):2055-67 Lau B et al. The integrative role of the pedunculopontine nucleus in human gait. Brain. 2015 May;138(Pt 5):1284-96. Demain A et al. High-level gait and balance disor - ders in the elderly: a midbrain disease? J Neurol. 2014 Niérat MC et al. Does trans-spinal direct current stimu- Jan;261(1):196-206. lation alter phrenic motoneurons and respiratory neuromechanical outputs in humans? A double-blind, Fronto-Parietal Anatomical Connections Influence the sham-controlled, randomized, crossover study. J Neurosci. Modulation of Conscious Visual Perception by High-Beta 2014 Oct;34(43):14420-9. Frontal Oscillatory Activity. Quentin R, Chanes L, Vernet M, Valero-Cabré A. Cereb Cortex. 2014, in press Popa T et al. The neurophysiological features of myoclonus-dystonia and differentiation from other dystonias. JAMA Neurol. 2014 May;71(5):612-9.

84 ICM ANNUAL REPORT 2014 6 - CENIR-small animal MRI – MRI PLATFORM FOR SMALL ANIMALS ALEXANDRA PETIET AND MATHIEU SANTIN

The small animal MRI platform is part and a large variety of imaging and data of the Neuroimaging research center analysis protocols offer a high-quality (CENIR). The platform is dedicated to platform for imaging in small animals. imaging of experimental disease models in The small animal CENIR-MRI is part of rodents. A very strong magnetic field asso- the network of platforms that facilitate ciated with high quality radio-frequency translational research. antennas (Cryoprobe™ for the mouse)

ACTIVITIES

• Basic neuroscience: neuroanatomy of • MRI microscopy: high resolution images the brain, evaluation of new biomarkers of post-mortem biological samples • Applied neuroscience: characterization • Image processing: development of and evaluation of experimental models, methods for data processing and of tools study of disease progression, effects of for functional and structural neuroima- therapeutic molecules ging in small animals

PUBLICATIONS

Kundu P et al. Differentiating BOLD and non-BOLD signals Cases O et al. Foxg1-cre mediated Lrp2 inactivation in in 11.7 Tesla Rat Resting State fMRI. Neuroimage 2014, the developing mouse neural retina, ciliary and retinal Nov 15;102 Pt 2:861-74. pigment epithelia models congenital high myopia. Plos One, 2015. In press. Santin MD et al. “In vivo (1) H MRS study in microlitre voxels in the hippocampus of a mouse model of Down syndrome M . Vandenberghe et al. “High-throughput 3D whole-brain at 11.7 T”, NMR Biomed 2014, Oct;27(10):1143-50. quantitative histopathology in rodents”, Nature Scientific Reports, 2015, in press

ICM ANNUAL REPORT 2014 85 PRECLINICAL FUNCTIONAL EXPLORATION – PHENOPARC TECHNICAL PL ATFORMS 3 5 PRECLINICAL FUNCTIONAL EXPLORATION – PHENOPARC

The preclinical functional exploration multiple techniques, including behavio- platform has 3000m2 of space for the ral, surgical, and electrophysiological housing of animal models for research approaches. The platform’s equipment projects and experimentation. Studies can and experts offer high quality support for be carried out on various models using teams within and outside the ICM.

1 - PHENO-ZFish – PLATFORM FOR EXPERIMENTATION ON THE ZEBRAFISH CLAIRE WYART AND SOPHIE NUNES-FIGUEIREDO

This platform is dedicated to preclinical Furthermore, the platform proposes research on the zebrafish. imaging, optogenetics, an advanced tech- The zebrafish is a vertebrate with a rapidly nique for activating target neurons at a developing nervous system that enables distance with light, and behavioral experi- quick testing of the potential of therapeu- ments on mutant and transgenic lines. tic molecules before studying the thera- The users of the platform have access peutics in detail in higher species. to specific training, for example in fish handling, including breeding, egg collec- The platform has aquariums that that tion, transgenesis, screening and sperm can house more than 20,000 adult fish freezing. Highly qualified technicians are and advanced equipment, including an responsible for care, breeding, and health. automated robot for feeding and 6 injec- PHENO-Zfish is part of the network of ICM tion systems for transgenesis. platforms (vectorology, genotyping, cell culture, electrophysiology…) that facilitate translational research.

86 ICM ANNUAL REPORT 2014 ACTIVITIES

• Production and maintenance of trans- • Behavioral analysis, interpretation of genic and mutant lines results obtained with mutant models • Genotyping by PCR and drug screening • Transgenesis (Tol2/CRISPR/TALEN) • Sperm freezing • Fluorescence in situ hybridization (FISH) • Electron microscopy on embryos or larvae (1-3 days) • Fluorescence immunohistochemistry on embryos/larvae in toto or on sections • Calcium imaging and optogenetics • Confocal, two-photon, and spinning • New lines for use with probes and acti- disk imaging vators of neuronal activity in vivo • Quantification of immunoreactive regions on images

PUBLICATIONS

Meffre D et al. Liver X receptors alpha and beta promote Wegener A et al. Gain of Olig2 function in oligodendro- myelination and remyelination in the cerebellum. 2015. cyte progenitors promotes remyelination. 2015. Brain Proc Natl Acad Sci USA [Epub ahead of print] 138 (Pt 1):120-35. Sahel A et al. Alteration of synaptic connectivity of oligo- Tepavˇcevi´c V et al. Early netrin-1 expression impairs dendrocyte precursor cells following demyelination. 2015. central nervous system remyelination. 2014. Ann Neurol Front Cell Neurosci 9:77. 76(2):252-68. Weider M et al. Elevated in vivo levels of a single trans- Hammond TR et al.. Astrocyte-derived endothelin-1 inhi- cription factor directly convert satellite glia into oligo- bits remyelination through notch activation. 2014. Neuron dendrocyte-like cells. 2015. PLoS Genet; 11(2):e1005008. 81(3):588-602.

2 - PHENO-ICMice – RODENT PRECLINICAL PHENOT YPING SERVICE MAGALI DUMONT AND BRAHIM NAIT OUMESMAR

This platform has a 1500 m2 infrastruc- is responsible for the breeding, care, and ture equipped with advanced equipment well-being of the experimental models. (7000 ventilated SOPF/SPF cages and PHENO-Mice is part of the ICM network 40 rooms equipped for experimenta- of platforms (small animal MRI, sequen- tion). It offers academic and industrial cing, vectorology, histology, microscopy…) teams advanced material supervised by that facilitate translational research. experts in the field. An external company

ICM ANNUAL REPORT 2014 87 PRECLINICAL FUNCTIONAL EXPLORATION – PHENOPARC TECHNICAL PL ATFORMS 3

ACTIVITIES

• Behavior: locomotion, anxiety, depres- • Neurophysiology: EEG, EMG, evoked sion, memory, sociability, motor coor- potentials, optogenetics, etc. dination, etc. • Room rental for experimentation • Surgery: stereotactic surgery, imaging • Services offered for the use of experi- in vivo, electroporation, resection mental models

PLATFORM FOR IN VIVO NEUROPHYSIOLOGY ON SM ALL ANIMALS SOPHIE NICOLE, VINCENT NAVARRO, AND DELPHINE ROUSSEL

This platform promotes neurophysiologi- • Peripheral neuropathies (axon degene- cal exploration of central nervous system ration, demyelination) pathologies in rodent models. Its aim is to • Myopathy, muscle atrophy, sarcopenia fulfill the needs of academic and industrial researchers who want to detect electro- • Myasthenia (neuromuscular transmission) physiological alterations and the effects • Epilepsy (presence/type/severity of the of therapeutic strategies. seizures) These approaches permit the charac- • Physiological behavior (sleep-wake terization of phenotypes of experimen- cycles) tal animals for: • Brain dysfunction (encephalopathy, etc.)

88 ICM ANNUAL REPORT 2014 ACTIVITIES

• Advice: the platform offers expertise • A unit for electromyography for developing projects and experimen- (EMG) and evoked potentials (EP) tal protocols, the choice of the most (Neuro- Mep- Micro-Neurosoft) pertinent neurophysiological tests, data • A unit for long-duration video elec- analysis, manuscript preparation, and troencephalography (EEG) in which ethics protocols. 5 mice or 3 rats can be recorded simu- • User training: the platform trains users ltaneously (Deltamed-Natus) in the use of the equipment, software, • Services: the platform offers exper- and data analysis tise for carrying out research projects • Rental of space/equipment: Two recording units are available:

3 - PHENO-ICMaze – RODENT BEHAVIOR PLATFORM MAGALI DUMONT AND NADEGE SARRAZIN

This platform assists academic and indus- and rats in order to ensure the success trial researchers in the design and carrying of the research projects. PHENO-ICMaze out of research projects requiring beha- is part of the network of ICM platforms vioral testing to characterize new transge- (small animal MRI, sequencing, histology, nic lines and identify therapeutic targets. microscopy…) that facilitate translatio- More than 30 tests are available for mice nal research.

ACTIVITIES

• Advice: the team offers its expertise for • Rental of rooms/equipment: 12 rooms the elaboration of projects and experi- can be rented for carrying out of over mental protocols, the choice of the most 30 behavioral tests. pertinent behavioral tests, data analy- • Services: the team offers its expertise sis, manuscript preparation and ethics for carrying out of research projects protocols. • User training: the team offers training sessions in the use of equipment and software

ICM ANNUAL REPORT 2014 89 PRECLINICAL FUNCTIONAL EXPLORATION – PHENOPARC TECHNICAL PL ATFORMS 3

PUBLICATIONS

Ingallinesi M et al. Local inactivation of Gpr88 in the Wegener A et al. Gain of Olig2 function in oligodendro- nucleus accumbens attenuates behavioral deficits elicited cyte progenitors promotes remyelination. Brain. 2015 by the neonatal administration of phencyclidine in rats. Jan;138(Pt 1):120-35. Mol Psychiatry. 2014 Aug 26. Scharfmann R et al. Development of a conditionally Boillot M et al. Glutamatergic neuron-targeted loss of LGI1 immortalized human pancreatic ß cell line. J Clin Invest. epilepsy gene results in seizures. Brain. 2014 Nov;137(Pt May;124(5):2087-98. 11):2984-96. Stack C et al. Methylene blue upregulates Nrf2/ARE genes Sahel A et al. Alteration of synaptic connectivity of oligo- and prevents tau-related neurotoxicity. Hum Mol Genet. dendrocyte precursor cells following demyelination. Front 2014 Jul 15;23(14):3716-32. Cell Neurosci. Mar 17;9:77.

6 BIOINFORMATICS AND BIOSTATISTICS - iCONICS

Over the course of the last two decades, The iCONICS silo also offers tools for research in neuroscience has witnes- managing the data for analysis and inter- sed a spectacular explosion of data pretation with specialized methods and collected in laboratories. Collecting the complex statistics. information is one thing, analyzing and The iCONICS silo is composed of two understanding it in order to develop new platforms. It offers researchers and clini- treatments is another. The role of the cians help with data analysis and creates iCONICS Bioinformatics silo is to ensure innovative computer programs. the collection of data from different sour- ces, then storing and organizing the data.

1 - DATABASES AND DATAWAREHOUSE LAURE SEUX AND BERTRAND FONTAINE The Databases and Datawarehouse team raw and analyzed data, etc.) obtained on stores data in databases, all of which healthy or diseased subjects. are designed on the same model. This The team then prepares the data in the permits daily formatting and manage- datawarehouse for statistical analysis and ment of information (clinical, genetic, provides the teams with tools for the first imaging, diagnoses, neuropsychology, steps of analysis. environment, images, disease evolution,

90 ICM ANNUAL REPORT 2014 ACTIVITIES

• Design the architecture of the data- • Development of secured Web interfaces bases and associated files • Conception of datawarehouses and • Installation and configuration of the datamarts databases • Development of dynamic reports (BI)

2 - BIOINFORMATICS/BIOSTATISTICS IVAN MOSZER AND BERTRAND FONTAINE The Bioinformatics/Biostatistics team • biostatistics, with an emphasis on the develops two kinds of expertise: design and implementation of advanced • processing of genetic/omics (geno- methodologies for the integration of mic, transcriptomic, epigenomic) data, multimodal data (clinical observations, primarily derived from high-through- genetics/omics and neuroimaging). put sequencing, by offering computer programs and accompanying research projects;

ACTIVITIES

• Offer methodological advice and exper- • Design and apply biostatistical methods, tise in the design of and interpretation in particular strategies for the integrated of biomedical studies. analysis of multimodal data • Define, apply, and offer procedures for treating high-throughput -omics data

7 BIOLOGICAL RESOURCE CENTER

Samples taken from patients, including a Committee of Protection of Persons blood, biopsies, and surgical resections, (CPP). Quality control of the three ICM are an extremely precious source of infor- Biological Resource Centers (BRC) is mation for disease research. The ICM certified in conformity with the norm hosts three biobanks that collect, record, AFNOR NF S96-900. The biobanks are process, conserve, and distribute biolo- also part of the BRC network of biocollec- gical resources, including samples and tions for neuroscience which benefits associated data. This activity is strictly from sharing resources and promotes regulated by bioethics laws to respect the collections, as well as the national patients and requires the approval of BioBank infrastructure.

ICM ANNUAL REPORT 2014 91 BIOLOGICAL RESOURCE CENTER TECHNICAL PL ATFORMS 3

1 - THE DNA AND CELL BANK ALEXIS BRICE, ALEXANDRA DURR, AND SYLVIE FORLANI

The DNA and Cell Bank – ICM amasses These samples represent one of the most and manages collections of samples from important collections worldwide, notably for medical research projects, mainly concer- pathologies such as Parkinson’s disease, ning neurological and psychiatric patholo- frontotemporal dementias, autism, and gies. In 2014, these collections contained certain rare diseases such as spinoce- about 182,000 samples of biological resour- rebellar degeneration. In 2014, the bank ces, including DNA, cells, blood cells, and was involved in 34 national and internatio- fluids, and fibroblaststaken from more nal research projects. The bank is equip- than 52,000 people, including patients, ped with important equipment, including relatives, and controls, since the creation an automated DNA extractor. Its quality of the bank in 1990 and increased by an control system was certified in confor- average of 3500 new samples each year. mity with the norm NF S96-900 in 2009.

PUBLICATIONS

Novarino G et al. Exome sequencing links corticospi- Serrano-Munuera C et al. New spinocerebellar ataxia nal motor neuron disease to common neurodegenera- with altered vertical eye movements mapping to 1p32. tive disorders. Science. 2014 Jan 31;343(6170):506-11. JAMA Neurol 2013, 70:764-771 Clot F et al. French clinical and genetic research network Di Gregorio E et al. A de novo X;8 translocation crea- on FTLD/FTLD-ALS. Partial deletions of the GRN gene tes a PTK2-THOC2 gene fusion with THOC2 expression are a cause of frontotemporal lobar degeneration. knockdown in a patient with psychomotor retardation Neurogenetics. 2014 May;15(2):95-100. and congenital cerebellar hypoplasia. J Med Genet 2013, 50: 543-551 Tezenas du Montcel S et al. Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes. Noreau A et al. SYNE1 mutations in autosomal reces- Brain. 2014 Sep;137(Pt 9):2444-55. sive cerebellar ataxia. JAMA Neurol 2013, 70: 1296-1301 Picard F et al. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 2014 Jun 10;82(23):2101-6.

92 ICM ANNUAL REPORT 2014 2 - BIOLOGICAL RESOURCE CENTER FOR MULTIPLE SCLEROSIS BERTRAND FONTAINE AND ISABELLE REBEIX

This resource center is a bank of samples as controls to determine what is specific from patients with multiple sclerosis to the disease. (MS), a disease with a strong socio-eco- To date, the DNA of 27,000 patients, 1739 nomic impact. Like the other ICM banks, visibly healthy relatives and 700 control the samples are distributed to resear- patients is at the disposal of the scientific chers who work to better understand the community. Each DNA sample is asso- physiopathology of the disease, improve ciated with detailed clinical data specific existing treatments, identify new cura- to MS as well as genetic data. tive treatments, and refine the prognosis of the evolution of the handicap. Over The center is also certified in confor - the course of the last 6 years, the center mity with the norm NF S96-900, specific has distributed 200,000 samples. The to biological resource centers. A natio- samples come from families that are nal project aimed at collecting biologi- either simplex, one affected child and his cal resources from 30,000 MS patients two parents, or multiplex, several affected was recently launched. In the context of members of a sibship, as well as spora- this project, the center was selected to dic cases and healthy subjects that serve manage the DNA of these patients

3 - THE Tumor BANK: OncoNeuroTek JEAN-YVES DELATTRE, MARC SANSON AND YANNICK MARIE he tumor bank, OncoNeuroTek, is a biolo- The location of the samples and asso- gical resource center (APHP) specia- ciated clinico-biological data are stored lized in samples from patients with brain in a unique database, permitting the tumors. It’s the largest biobank of brain identification and extraction of samples tumors in Europe and contains samples necessary for projects associated with from about 15,000 patients. The large the tumor bank. size is thanks to its location in the Pitié- To promote the quality of its services and Salpêtrière Hospital.The bank receives the professionalism of its personnel, the samples locally, and the hospital is one OncoNeuroTek tumor bank adheres to the of the largest European centers for the principles and requirements of the French diagnosis and treatment of brain tumors. norm NF S96-900, specific to biological OncoNeuroTek collects, annotates, and resource centers since 2012. After a two conserves samples from patients with year period during which a correct and brain tumors. For over 15 years, it has viable quality control system was imple- collected tissues and also tumor DNA and mented, the tumor bank was certified RNA as well as patient DNA and plasma. by AFNOR, the national organization for

ICM ANNUAL REPORT 2014 93 BIOLOGICAL RESOURCE CENTER TECHNICAL PL ATFORMS 3

standardization, certification, industry been established with research teams press, and training. from all horizons: regional, national, and Since the OncoNeuroTek tumor bank was international. set up in the ICM, 16 collaborations have

PUBLICATIONS

Labreche K et al. TCF12 is mutated in anaplastic oligo- Di Stefano AL et al. Association between glioma suscepti- dendroglioma. Nature Comm, in press. bility loci and tumour pathology defines specific molecular etiologies. Neuro Oncol. 2013 May;15(5):542-7. Di Stefano et al. Detection, characterization and inhibition of FGFR-TACC fusions in IDH wild type glioma. Clin Wang XW et al.Prognostic impact of the isocitrate dehy- Cancer Res. 2015 [Epub ahead of print] drogenase 1 single-nucleotide polymorphism rs11554137 in malignant gliomas. Cancer. 2013 Feb 15;119(4):806-13. Gleize V et al. CIC inactivating mutations identify aggressive subset of 1p19q codeleted gliomas. Ann Neurol. 2015 Gonzalez-Aguilar A1 et al. Recurrent Mutations of May 27 [Epub ahead of print] MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas. Clin Cancer Res. 2012 Oct 1;18(19):5203-11. Labussière M et al. TERT promoter mutations in gliomas, genetic associations and clinico-pathological correla- Alentorn A et al. Prevalence, clinico-pathological value, tions BRITISH JOURNAL OF CANCER Volume: 111 Issue: and co-occurrence of PDGFRA abnormalities in diffuse 10 Pages: 2024-2032 Published: NOV 11 2014 gliomas. Neuro Oncol. 2012 Nov;14(11):1393-403. Labussière M et al. Combined analysis of TERT, EGFR, Idbaih A et al. SNP Array Analysis Reveals Novel Genomic and IDH status defines distinct prognostic glioblastoma Abnormalities Including Copy Neutral Loss of Heterozygosity in classes. Neurology 2014; 83:120 Anaplastic Oligodendrogliomas. PLoS One. 2012;7(10):e45950. Reyes-Botero G et al. Molecular analysis of diffuse intrin- Boisselier B et al. Detection of IDH1 mutation in the sic brainstem gliomas in adults. J Neurooncol. 2014 plasma of patients with glioma. Neurology. 2012 Oct Jan;116(2):405-11. 16;79(16):1693-8. Enciso-Mora V et al. Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222. Br J Cancer. 2013 May 28;108(10):2178-85.

94 ICM ANNUAL REPORT 2014 Kristen Severi Team of Claire Wyart

Transgenic Gad1b:GFP (Higashihima Lab) zebrafish larva

CLINICAL INVESTIGATION CENTER

1 Parkinson’s disease

2 Neurogenetics

3 Alzheimer’s disease

4 Multiple sclerosis 5 Amyotrophic lateral sclerosis 4 6 Rare diseases

7 Understanding brain function: motivation Participatory medicine 8

In 2014, 77 studies were ongoing in the ICM Clinical Investigation Center (CIC), directed by Pr. Jean-Christophe Corvol. The clinical trials concerned Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neurogenetics, neuropsychiatry, amyotrophic lateral sclerosis, peripheral neuropathies, epilepsy, and other neurological diseases.

ICM ANNUAL REPORT 2014 97 PARKINSON’S DISEASE CLINICAL INVESTIGATION 4 CENTER 1 PARKINSON’S DISEASE

Deep brain stimulation of the subtha- with the autonomous nervous system. lamic nucleus is a treatment that has Studies are being performed in the CIC beneficial effects for the motor symp- to better understand these symptoms. toms of Parkinson’s disease, however, For example, a very detailed imaging it does not improve balance problems study of the brainstem has revealed or falls. A therapeutic trial conducted at brain structures implicated in sleep and the CIC by an ICM team (Carine Karachi balance disorders in certain patients and David Grabli) showed that stimu- (Marie Vidailhet and Isabelle Arnulf). A lation of another deep brain nucleus, therapeutic study is also under way to the pedunculopontine nucleus (PPN), try to improve hypersalivation (Marie improves gait and balance disorders Vidailhet). that resist pharmacological treatment in certain patients. The double-blind Finally, an important effort has been study, performed in six patients, showed made to progress in the personaliza- a decrease in “freezing” and falls in tion of treatments thanks to progress three patients, as well as an improve- in genetics. A cohort of more than 400 ment in postural control and quality of patients is being followed at the CIC to life. These results are very encouraging identify predictive factors, and another and open the way to the development study is under way in 400 patients, half of new treatments for severe forms of which have behavioral disorders of Parkinson’s disease. However, they induced by their anti-parkinson’s treat- must be regarded with caution because ment, which are dopaminergic agonists. of surgical complications observed during the study. Following this study, a The major challenge for the coming grant was obtained from the Michael J. years is to stop the evolution of the Fox Foundation for a larger scale thera- disease or even prevent the appearance peutic trial targeting the PPN. of symptoms in at-risk subjects. The The CIC also participates in the evalua- present phase remains the search for tion of new pharmacological treat- biomarkers that enable the progression ments for Parkinson’s disease. Trials of the disease to be followed or markers of treatments for the motor complica- preceding the appearance of symp- tions of the disease, motor fluctuations toms. To rise to the challenge, a study and dyskinesias, were completed in has just begun at the CIC on a cohort 2014 or are ongoing (Jean-Christophe of 300 patients (Jean-Christophe and Corvol). Current treatments are not Marie Vidailhet). The effort is shared with effective on “non-motor” symptoms of European (Sweden, Germany, Spain, the disease, such as cognitive, sleep, AETIONOMY project) and American or behavioral disorders or problems (Michael J. Fox Foundation) partners.

98 ICM ANNUAL REPORT 2014 A therapeutic trial testing the efficacy of neuroprotective drugs are being tested bee venom as a neuroprotective treat- ex vivo, on blood from Parkinsonian ment was completed and the results are patients or subjects at risk for deve- being analyzed (Andreas Hartmann). loping the disease in partnership with In addition, several new potentially the pharmaceutical industry.

2 NEUROGENETICS

The ICM (Alexis Brice and Suzanne This great step forward in the story of Lesage) is an active partner in an inter- this neurodegenerative pathology is national consortium that aims to define the result of meta-analysis of all exis- the genetic profile of Parkinson’s ting pan-genomic association studies disease. This project gave access to performed on data from more than whole exome sequencing, sequencing 100,000 people. Additionally, analysis of all genes, in thousands of parkinsonian data from families of patients followed patients and recently identified six at the Pitié-Salpêtrière by the neuroge- new genetic risk factors for Parkinson netics team led to the identification of disease. The studies identified 24 gene- new genes responsible for the disease, tic risk factors implicated in the disease, opening the way to new therapeutic six of which had not been described. strategies.

3 ALZHEIMER’S DISEASE

The first therapeutic trial aimed at disease because they carry a mutation preventing the onset of Alzheimer’s responsible for the disorder. This is the disease is under way (Bruno Dubois, first neuroprotective therapeutic trial Isabelle Le Ber), the aim of which is to to be undertaken in humans. neuroprotective test the efficacy of a Other pharmaceutical agents are being agent rare genetic forms in of Alzheimer tested at the CIC or the Memory and disease with international industrial and Alzheimer Disease Center (IM2A) coor- academic partners. The study is original dinated by Bruno Dubois. in that it also proposes to treat asymp- tomatic people that are at-risk for the

ICM ANNUAL REPORT 2014 99 MULTIPLE SCLEROSIS CLINICAL INVESTIGATION 4 CENTER 4 MULTIPLE SCLEROSIS

Three new treatments already tested pre-clinical study to test the efficacy of in the CIC are now commercially avai- a new treatment was performed on 70 lable, including a treatment to improve patients with different types of multiple gait disorders, fampridine, and two new sclerosis. treatments for inflammatory forms of Finally, the CIC participated in two multiple sclerosis (Catherine Lubetzki, therapeutic trials aimed at developing Isabelle Papeix, Maya Tchikiladze). a new treatment for multiple sclero- Research concerning progressive forms sis symptoms developed by MedDay, a of the disease is ongoing. CIC teams company incubated in the ICM. The effi- hope to discover differential biomar- cacy of MD1003, a new agent against the kers of inflammation, myelin destruc- progressive form of MS was just confir- tion, and neurodegeneration (Bruno med by a Phase III study involving 154 Stankoff). Studies aimed at testing patients. This treatment not only slows agents to slow the progression of the the progression of the disease but also disease, two studies, and promoting improves the health status of certain remyelination, one study, are ongoing. A patients.

5 AMYOTROPHIC LATERAL SCLEROSIS

The results, unfortunately negative, of a approaches, imaging of the spinal therapeutic trial in which the CIC parti- cord, and biomarkers in blood or biop- cipated were announced in 2014. The sies (Pierre-François Pradat, François fight continues, however, with several Salachas, Lucette Lacomblez, Thomas therapeutic trials now underway in the Lenglet). Additionally, the CIC contri- CIC (François Salachas, Pierre-François butes to the development of a tool for Pradat). The CIC is also contributing to a writing with the eyes for patients with better understanding of the mechanisms severe motor disorders (in collaboration implicated in this disease by combining with Jean Lorenceau). clinical analysis, electrophysiological

100 ICM ANNUAL REPORT 2014 6 RARE DISEASES

Aside from Parkinson’s disease, The gene responsible for a very rare the CIC also contributes to a better disorder of bimanual motor coordination understanding of and the development was identified thanks to a collaboration of new treatments for related rare of ICM researchers (Christel Depienne diseases. The CIC participated in one of and Emmanuel Roze). The physiopa- the first international therapeutic assays thology of this disease was then studied in progressive supranuclear palsy in experimental models and the results (Jean-Christophe Corvol). Although the were confirmed in humans. results of the trial were unfortunately negative, they nonetheless provided A therapeutic trial was conducted at information on the disease progres- the CIC to test the efficacy of an anti-e- sion, which will facilitate development pileptic drug in the treatment of dysto- of future clinical trials. nias with myoclonus (Emmanuel Roze). The results are being analyzed. On the occasion of the 50 years of the discovery of this disease, the CIC, in Other pathophysiological studies conjunction with the French association or therapeutic assays are being of PSP patients, organized a workshop performed in several rare diseases, in which clinicians, researchers, and including cerebellar ataxias, channe- industry reflected on the best way to lopathies, metabolic disorders, and identify new pharmaceutical agents for others (Alexandra Dürr, Fanny Mochel, this disease in June 2014. Bertrand Fontaine, Savine Vicart).

7 UNDERSTANDING BRAIN FUNCTION: MOTIVATION

In addition to therapeutic trials and brain. For example, a series of studies studies aimed at better understanding were carried out in healthy volunteers the mechanisms of certain patho- to determine which neurotransmitters logies, the CIC is also at the service are implicated in the phenomenon of of ICM researchers who try to better motivation (Mathias Pessiglione). understand the function of the human

ICM ANNUAL REPORT 2014 101 PARTICIPATORY MEDICINE CLINICAL INVESTIGATION 4 CENTER

8 PARTICIPATORY MEDICINE

The CIC has begun to evaluate patients used, notably for epilepsy. In collabora- at home in order to study the evolution tion with Alexis Genin (the IHU-A-ICM of the disease in an ecological envi- and the Pitié-Salpêtrière Hospital), a ronment via intelligent applications. work group (“living lab”) is being set Tools for evaluation and also reedu- up in which patients, developers, and cation through intelligent games are health professionals meet together to being used, notably for gait disorders in generate ideas and apply them in order parkinsonian patients. Various tools for to best respond to the needs of patients. the follow-up of patients are also being

The Clinical Investigation Center received support from the EDF Foundation

102 ICM ANNUAL REPORT 2014

RESEARCH APPLICATIONS

1 Transform knowledge and promote research 2 iPEPS-ICM companies 5

The ambition of the ICM is not only to perform excellent research, but above all to use the knowledge and abilities of researchers for the development of new treatments. To achieve this aim, the “Research Applications” team is composed of people with doctoral degrees in science who have worked in industry and specialists in innovation and the creation of start-ups. The team detects scientific results that inspire hope, creates partnerships with the most active companies in the health field, protects discoveries by patents, and initiates work on projects to develop new treatments. To promote all the work of the institute and permit researchers at the institute to create their start-ups, the iPEPS-ICM incubator establishes a bridge between research and concrete applications. This promotion of knowledge and know-how permits the rapid transformation of creation of the fruits of research into medical applications. It should ensure the autonomy and competitive status of the ICM.

ICM ANNUAL REPORT 2014 105 TRANSFORM KNOWLEDGE AND PROMOTE RESEARCH RESEARCH APPLICATIONS 5 1 TRANSFORM KNOWLEDGE AND PROMOTE RESEARCH

The ICM has been awarded the prestigious “Carnot Institute” label, which supports its strategy of establishing industrial partnerships. Thanks to this support, Ultragenyx for a clinical Phase II study the Research Applications team utilizes of a molecule identified by the ICM and a proactive approach to detect innova- Inserm against Huntington disease. A tion resulting from ICM research and to particular effort was made to ensure the establish collaborations with industry. quality of the management of the part- In 2014, 70 partnerships were established, nership in order to encourage teamwork including 20 new scientific collabora- and retain loyalty on the part of the indus- tions. For example the ICM established a trial partners, more than half of which partnership with the Californian company are international.

106 ICM ANNUAL REPORT 2014 2 iPEPS-ICM companies

iPEPS-ICM stands for “Paris-Salpêtrière and “off” phases of patients with Business Incubator.” This structure, Parkinson disease. Ad Scientiam was created in 2012, is the first accelera- included in a ranking of the 100 most tor of innovation dedicated to diseases innovative start-ups in France. of the brain in France. This incubator/ accelerator facilitates the relationships SIX NEW COMPANIES of companies with both investors and With the addition of six new start-ups clinical experts and helps them to esta- in 2014, the iPEPS-ICM now hosts blish research collaborations with ICM 20 industrial partners of the institute teams. and is now full. This year, the first international 2014 was the year companies established offices in of successful start-ups the ICM: Neoventures Technologies in the iPEPS-ICM (Ontario) that develops new biomarkers The efficacy of a new agent, MD1003, of Alzheimer’s disease and PathMaker against the progressive form of (Boston) that works on a program of multiple sclerosis was just confirmed electrical stimulation of the spinal cord by a clinical Phase III trial. This treat- to facilitate walking. ment not only slows the progression of the disease but also improves the THREE NEW PATENTS state of health of the patients. At the Three new patents were obtained: origin of this treatment is MedDay, a start-up founded by the neurologist Hand me, a life agenda for epileptic Frédéric Sedel and Guillaume Biron. patients in the form of a smartphone This company has been incubated at the application, ZebraZoom, software for ICM since its creation. the automatic tracking of zebrafish behavior developed in collaboration Three projects incubated at the iPEPS- with Claire Wyart, triheptanoin, a mole- ICM or derived from research in the cule for treating Huntington disease. institute won prizes at the world innovation competition: DREEM, a connected headband that optimizes sleep, Brain TWO NEW PROTOT YPES e-NOVATION that creates e-health Toap Run, a video game for the preven- solutions on the basis of video games, tion of falls in patients with Parkinson’s and Bio serenity that develops an intel- disease was finalized and the first clini- ligent health solution for the follow-up cal trial is underway. and diagnosis of epilepsy. The prototype of the Melomind headset, Ad Scientiam has developed two smart- created by My Brain Technologies, was phone applications to both measure presented at the CES 2015 in Las Vegas. motivation and also to follow the “on” The connected headset that induces

ICM ANNUAL REPORT 2014 107 iPEPS-ICM companies RESEARCH APPLICATIONS 5

relaxation through the use of specific to “Lift sessions” that are the occasion sounds. for regular discussions and dialogue among the different members of the The iPEPS-ICM INFRASTRUCTURE structure. In addition to supporting young companies in terms of support and logistics, the iPEPS-ICM offers more THE FUTURE than 1000m2 of offices, laboratories, Over the course of these last years, medi- open space and meeting rooms. It also cine has been radically transformed. offers the use of advanced technology Digital solutions are now integrated platforms in the central part of the to help patients remain autonomous building, which favors encounters. thanks to tools like tablets or smart- phones and medical technology. Great iPEPS-ICM hosts both companies that developments will also occur in the field develop new pharmacological treat- of prevention, the best treatment being ments and companies that specialize to remain well. The next great ambition in medical technologies. The struc- of the ICM is to ally itself with partners ture also houses start-ups developing to develop research programs aimed new diagnostic solutions in order to at developing new strategies to prevent treat diseases earlier, and “connected or delay the development of diseases. health” tools, such as video games, to These strategies could include nutri- help the elderly maintain their auto- tional approaches, physical activity, nomy. Here again, openness is a source “bio-feedback” and more. of potential partnerships and creativity at the service of patients. Life in the You will find all the companies of the incubator has also evolved, notably due iPEPS-ICM on the site icm-institute.org

You will find all the companies of the iPEPS-ICM on the site icm-institute.org

108 ICM ANNUAL REPORT 2014 KEY FIGURES

1 Fundraising

2 Use of Resources Statement 3 Balance sheet 6 All the acts and discoveries of the ICM were made in total transparency; the “Comité de la Charte du Don en Confiance” (Charter committee for donating with confidence) awarded the ICM its approval in 2010 and again in 2014. The last report attests that the ICM Foundation accepts the principles of the Charter committee, statutory functioning and disinterested management, rigorous management, high quality communication and fundraising campaigns, and financial transparency. You will find below the use of resources statement and a detailed presentation of the accounts of the ICM for the fiscal year.

ICM ANNUAL REPORT 2014 109 FUNDRAISING KEY FIGURES6 1 FUNDRAISING

Revenue from fundraising in 2014 reached In the context of the development of the 11.1 M€ at the end of the fiscal year. More Circle beyond our borders, the ICM orga- than 76.8 M€ in accumulated donations and nized a charity dinner in London for poten- pledges have been raised since the crea- tially important donors in April 2014. tion of the ICM. In order to increase its donor base, the ICM In 2014, three important contracts with has pursued its strategy of direct marketing sponsors were signed over the course of initiated in 2010. An investment of 2.3 M€ the year with: divided among 11 fundraising campaigns yielded 4.5 M€ for the fiscal year and  Fondation EDF to support a research increased the donor base by more than program studying the mechanisms of the 26,000 people for a total of 85,000 donors appearance of Parkinson’s disease. at the end of 2014.  Fonds de dotation Pierre Bergé to finance Finally the ICM is particularly grateful to upgrading of the 3T MRI families who collected donations in memo-  Fondation AREVA to support research riam for the benefit of the Institute. on cerebral dystonia. On July 4, 2014, the Friends of the ICM Circle DONATIONS IN KIND AND was launched. It assembles donors who SPONSORSHIPS were engaged in the adventure of the ICM Many companies have offered their support from the beginning and who have donated by contributing know-how in their field of € large sums of money (10,000 or more). activity or by offering products free of charge. The Circle was created to specifically thank The ICM has benefited from important donors who have been active all  Media space offered by Amaury média, throughout the financing campaign laun- Europe 1, Lagardère Publicité, Canal+, NRJ, ched by the ICM in 2008. Médiavision, FigaroMédias, TF1 Publicity, The Circle now has 447 members. To France Télévisions, Clear Cjannel, Metrobus, express our gratitude, exclusive activities A nous Paris, Figaro.fr, Liberation.fr, Au are proposed including encounters and féminin.com, Skype, CCM Benchmarck, discussions between donors and resear- Doctissimo, Orange, GMC Factory, AOD, chers to keep donors updated on research HiMedia Group, RMC, AB, L’EQUIPE, TMC, perspectives and the use of donations. A ir France, Credit Agricole Center Ouest. The Circle is presided over by Mr. Maurice  Free services: Publicis, 1000 Mercis, Lévy and Mr. David de Rothschild, Founding Samsung, Orrick Rambaud Martel, VH 15, Members of the ICM. Quaterback, E-makina, IDEC, E-Art Sup.

110 ICM ANNUAL REPORT 2014 THE ICM IN FRANCE scientific advances with its own research The ICM has continued its regional expan- teams and their regional, national, and sion. In 2014, three regional antennae were international partners organized around the following objectives:  Bring together ICM and regional resear-  Reinforce the visibility, reputation, and chers in neuroscience and promote these attractiveness of the ICM for donors, the collaborations. general public, and economic and politi- This approach will be progressively extended cal figures to other regions on different themes related  Contribute to the development of finan- to nervous system diseases. cial resources of the ICM to accelerate

ICM ANNUAL REPORT 2014 111 Use of Resources Statement KEY FIGURES6 THE USE OF RESOURCES STATEMENT – 2014 2 The fiscal year ended on December 31, 2014

Resources Uses N-Profit Allocation Resources collected- and loss of resources collected USES RESOURCES profit and loss statement by use and used statement

Carryover of resources collected from the public not allocated and not used at the beginning of the fiscal year 1 922 760 Social Missions 18 965 223 6 916 634 ACTIONS DIRECTLY CARRIED OUT Resources collected from the general public 8 195 737 8 195 737 Research program 11 013 534 2 214 343 Unallocated monetary donations 7 374 482 7 374 482 Technological platforms 5 615 960 2 765 179 Allocated monetary donations 153 880 153 880 Other (including research Unallocated bequests and other gifts 507 248 507 248 Allocated bequests and other gifts 0 0 applications, incubator and events/ international partnerships) 2 335 729 1 937 112 Other products related to public generosity 160 126 160 126 Costs of fundraising 3 370 951 2 622 523 Other private funds 7 330 572 Costs of appeals to the generosity Patronage 2 937 934 of the general public 2 621 283 2 620 112 Partnership 2 568 326 Costs of the search for other Private grants 1 824 312 private funds 304 600 0 Subsidies and resources from Costs related to the search for public competitions 3 277 873 subsidies and other public competitions Costs of communication 445 069 2 411 Other products 5 190 670 Financial products 272 423 Costs of functioning Services offered 2 193 039 of the organism 1 824 796 197 826 Other products 2 725 208

I. TOTAL USES IN THE PROFIT I. TOTAL RESOURCES FROM THE AND LOSS STATEMENT 24 160 971 9 736 983 PROFIT AND LOSS STATEMENT 23 994 851

II. PROVISIONS 15 600 II. CARRYOVER OF PROVISIONS 0

III. EXPENSES TO BE CARRIED OUT III. CARRYOVER OF UNUSED ON ALLOCATED RESOURCES 3 063 917 ALLOCATED RESOURCES FROM PREVIOUS FISCAL YEARS 2 253 667

IV. SURPLUS RESOURCES OF IV. VARIATION OF ALLOCATED FUNDS THE FISCAL YEAR 0 COLLECTED FROM THE PUBLIC 37 698

V. RESOURCES LACKING FOR THE FISCAL YEAR 991 969

V. GRAND TOTAL 27 240 488 VI. GRAND TOTAL 27 240 488 10 156 195

Part of fixed assets acquired during the fiscal year financed by funds collected Neutralization of the provisions TOTAL OF USES FINANCED BY for depreciation of fixed RESOURCES COLLECTED assets financed by funds FROM THE PUBLIC 9 596 420 collected -140 563 BALANCE OF RESOURCES TOTAL USES FINANCED COLLECTED FROM THE PUBLIC BY FUNDS COLLECTED NOT AFFECTED OR USED AT THE FROM THE PUBLIC 9 596 420 END OF THE FISCAL YEAR 559 775

EVALUATION OF VOLONTARY CONTRIBUTIONS IN KIND Social missions 44 818 Volunteers 44 818 Costs of fundraising Services in kind Costs of functioning Contributions in kind

112 ICM ANNUAL REPORT 2014 RESOURCES 2014

The products of the fiscal year correspond 13% Fundraising essentially to revenues from fundraising 34% the general public 34% Fundraising (46%), either from the general public (34%) private foundations 21% and enterprises or private foundations and companies (12%). Revenue from activities Public and private subsidies Other products They also include: 12% 20%  Revenues from the activity of the technical platforms (2.2 M€) and research The resources for 2014 reached 26.2 M€. collaborations with industrial partners They include 24 M€ of products of the fiscal (2.6 M€). year and a carryover of 2.2 M€ affected  Public (3.3 M €) and private (1.8 M€) but not used during previous fiscal years. subsidies.

USES 2014

The research projects financed were dedi- 7,5% cated to neurodegenerative diseases and 14% spinal cord injury. The technical platforms Social missions (neuroimaging, vectorology, sequencing, Fundraising Functioning genotyping, cell culture, and histology) 78,5% contribute to these projects. The costs of fundraising correspond to expenses related to the collection of funds from private people (donations and bequests) and private companies and The grand total of uses for 2014 reached foundations (sponsorship and support). € € € 27.2 M : 24.1 M used in 2014 and 3.1 M They represent 14% of the uses. affected for later use. Among uses in 2014, The costs of functioning correspond to the the amount dedicated to social projects expenses of the support teams (finance, reached 19 M€, which represents 78.5% personnel, informatics and logistics), of the total uses for the fiscal year. The which represent 7.5% of the total uses for social projects include: the fiscal year. Uses to be carried out on  Research projects (58%) affected resources (3.1 M€) correspond  Technical platforms (30%) principally to donations from companies  Scientific events and international part- and foundations received during the year nerships (9%) to be used later for specific pluriannual  Incubation of innovative enterprises (3%) research programs.

ICM ANNUAL REPORT 2014 113 Use of Resources Statement KEY FIGURES6

USE OF RESOURCES COLLECTED FROM THE PUBLIC

2% Resources collected from the public at large and used in 2014 reached 9.6 M€. € 27% In brief, out of 100 of resources collected Social missions and investments from the general public, 71 € were used to of the ICM 71% Fundraising finance the social projects and investments and communication Functioning of the institute, 27 € were used for fundraising, and 2 € covered the costs of functio - ning of the ICM.

3 Balance Sheet

SIMPLIFIED BALANCE SHEET

ASSETS (In K€) 31.12.14 31.12.13 Net immobilized assets 10 168 11 778 Realizable and available assets 32 678 27 822 Total 42 846 39 600

LIABILITIES (IN K€) 31.12.14 31.12.13 Association funds 20 418 23 720 Results of the fiscal year -992 -3 112 Dedicated funds 4 694 3 884 Debts 18 726 15 108 Total 42 846 39 600

114 ICM ANNUAL REPORT 2014 The total amount of investments by the The net immobilized assets reached ICM since its creation has reached nearly 10.1 M€. As of December 31, 2014, the 21 M€, mainly dedicated to the technical treasury amounted to 18.4 M€. platforms that support research. The equity of the ICM was 19.4 M €. It included 11.7 M€ of association funds plus Investments during the fiscal year reached 2.6 M€ of subsidies for investments and a 1.1 M€: carryover of 5.1 M€. The non-expendable The ICM acquired a cryoprobe for imaging, endowment of the ICM is 1.2 M€. completed its equipment for the functio- At the end of the fiscal year, dedicated nal experimentation platform, and finished funds (funds remaining to be used for the installation of its business incubator. specified programs) reached 4.7 M€.

EXCERPT FROM THE 2014 REPORT OF THE CONTROLLER OF THE COMITE DE LA CHARTE POUR LE DON EN CONFIANCE “The last three year period saw the rapid and courageous launching of the social missions of the Foundation, which set up high level teams and their equipment in a superb building. The foundation offered its researchers facilities that they did not previously have access to and reinforced perspectives for the internationalization of their work in a variety of ways. The new period that is starting is characterized by the desire to set up a stable organization based on a rational and concerted public/private partnership endowed with balanced financial bases, while maintaining the same ambitions for high level performance in the sphere of national and international scientific research.”

ICM ANNUAL REPORT 2014 115 LIFE IN THE ICM LIFE IN THE ICM

1 Scientific and extra-scientific lectures

2 Fundraising events and the publicity campaign 7

The ICM has developed a strategy of scientific and extra-scientific activates that include both numerous exchanges among the research teams and also encounters with high level scientists and personalities from society. Additionally, in 2014, the ICM developed communication programs consisting of cultural and sporting events in partnership with associations and enterprises. These events are initiated by the ICM or organized for its benefit in order to raise funds and for it to become better known. In parallel, the institute benefited from an ambitious publicity campaign conceived by Publicis Conseil, along-term partner of the ICM.

ICM ANNUAL REPORT 2014 117 SCIENTIFIC AND EXTRA-SCIENTIFIC LECTURES LIFE IN THE ICM 7 1 SCIENTIFIC AND EXTRA-SCIENTIFIC LECTURES

Twenty-eight events of scientific interest took place during the year at the ICM, including 3 prestige lectures: Prof. Richard Frackowiak of the Vaudois University Hospital Center with a lecture entitled, “The nosology of brain diseases – an informatics and data lead approach,” Sten Grillner, of the Neuroscience Department of the Karolinska Institute in Stockholm, with a lecture entitled, “The logistics of network in motion – from microcircuits to selec- tion of behavior,” Eve Marder, of the University of San Diego, in California, with The six extra-scientific lectures were also a lecture entitled, “Variability, robust- the occasion to expand the field of discus- ness, and homeostasis in neurons and sion. This year, Jean-Claude Ameisen, networks.” The inaugural lecture of Brain President of the National consultative Awareness Week was given by Philippe committee on ethics – Professor at the Vernier, Director of the Alfred Fessard University of Paris (erreur dans la version Institute of Neurobiology, CNRS, on the française. MR) – Diderot, reflected on question, “Evolution of intelligence and memory: “What is left of what has disap- the size of the brain: is there a relation?” peared?” Actress Dominique Blancread ICM researchers organized nume- texts by Marguerite Duras. Stage director rous colloquia at the ICM. The institute Bruno Abraham-Kremer gave a reading hosted the 1st International colloquium based on the correspondence and works on the cellular Imaging Network of of Anton P. Tchekov. Laurent Cohen, Pierre and Marie Curie University, the Professor of neurology and researcher at European Congress on Gilles de la the ICM, debated the subject of neurop- Tourette Syndrome, the 4th International sychology, “The brain as spare parts.” Symposium on the Biology of Decision- John Harris, professor of bioethics at the Making, the 1st International Colloquium University of Manchester, participated in on Neuroethics, the 1st Colloquium on the 1st Colloquium on Neuroethics. Eric Neuroimmunology; Neuropsychology Burguière, ICM researcher, and Yves Day that brought together many clini- Sarfati, psychiatrist, presented a scien- cians, Scientific Day of the Life Sciences tific show. Mathieu Lehanneur, creator/ Section of the Ecole Pratique des Hautes designer, gave a lecture, Architecture Etudes. that combines design, science, art and

118 ICM ANNUAL REPORT 2014 technology to improve the lives of its directed toward young people, in colla- users.” And finally, Jean D’Ormesson boration with INSERM, the Rectorat gave a lecture entitled, “Why do we of Paris and life science teachers in write?” junior and senior high schools, as well as elementary schools. In the program The ICM also hosted the inaugural “Chercheurs en herbe” (Budding resear- lecture of the 50 years of INSERM, given chers), students are immersed in the life by Prof. Yves Agid, Honorary Professor of the laboratory and carry out a research of Neurology and Neuroscience and project during the school year, assisted Founding Member of the ICM, on the by young researchers. “Destination labo” subject, “Normal and pathological provides the occasion to bring young subconsciousness.” people into the laboratories in order to Each month, convivial moments are orga- familiarize them with research-related nized to permit researchers, teams, and professions. companies to meet together and discuss Finally, the research teams of the ICM their projects and research results. participated in the encounter “Patients- Finally, each year the ICM participates in Researchers” organized by Inserm in pedagogical activities with two programs October.

THE ASSOCIATION OF YOUNG RESEARCHERS: LES AJITES

The association “les Ajités” was born of through the social relations they esta- an initiative of a group of young resear- blish. This year, they inaugurated chers who identified the need for a the first edition of the Brain Booster framework in which to meet together Challenge. This unique workshop offers to discuss their work when the ICM the participants the possibility of deve- was created. They organized the first loping their capacity to create innovative retreat of young researchers in 2010 and and interdisciplinary research projects initiated the first socio-cultural activi- and thus assimilate, in an original way, ties of the future institute. the obligations of their profession.

Since then, this group of young resear- Throughout the year, the association chers has become official with the cita- organizes scientific and cultural events, tion of the association in the JO (Official which serve to maintain scientific inte- Journal) in February 2012. The annual ractions among the young researchers retreat, organized with the help of the of the Institute, thanks to the financial Communications Department, has aid and logistics of the ICM. The monthly become an essential event on the ICM’s “Science Pizza” provides the possibi- scientific calendar. lity of continuing discussions in a more This three-day retreat not only gives rise informal setting than a seminar. This to high level scientific discussions, but is date has become a staple of the young also the occasion for the young resear- scientific community, an average of chers to develop a “spirit of the institute” 80 people participate each month. The

ICM ANNUAL REPORT 2014 119 SCIENTIFIC AND EXTRA-SCIENTIFIC LECTURES LIFE IN THE ICM 7

Ajités also organizes informal lunches The “Happy Hours,” to which all for young researchers with the weekly members of the personnel of the lecturer as part of the scientific events Institute are invited, encourage the crea- of the Institute; the youngest members tion of a social fabric in the building. The of the institute thus have the possibility first Scientific Photography Competition of privileged discussions with internatio- in the Institute was a real success. The nally renowned researchers. In addition, winning photographs were exhibited in the association organizes oral training the hall and on the social networks. sessions in which the participants learn Finally, the association offers an extra-s- the basic techniques of handling stress cientific framework for diverse activities and using their voice, with the aim of open to all the personnel of the Institute. improving their oral presentations.

2 Fundraising events and the publicity campaign

SPORTING AND CULTURAL EVENTS

This year, nineteen sporting events supported ICM research, such as the operation “Un chrono pour un Don,” the meeting of the automobile association “Fée rarissime,” Classic Days, the association Sogno Di Cavallino, the “Teufs was honored, notably by the support of Teufs du Coeur” organized by the Lions Francis Joyon who started on the “Route Club of Essarts le Roi, or the women’s du Rhum” aboard the trimaran IDEC tennis internationals of Strasbourg. flying the colours of the ICM. The navi- All of these partners, new or faithful gator also crossed the finish line at Rio to us, enabled the collection of funds de Janeiro by starting on the “Route de for the benefit of the ICM while asso- l’Amitié.” The Institute was also pres- ciating pleasure and generosity every- ent at the competition “Les Voiles de where in France. The universe of sailing St. Barth,” a regatta in the heart of the

120 ICM ANNUAL REPORT 2014 Caribbean, with a Gala for the profit of the ICM. In 2014, our faithful partners once again associated the ICM with sporting events such as “La tête c’est le pied,” the Golf trophy “les Echos” and the “20 KM de Paris.” The ICM also benefited from an auction organized by the Porsche Club France.

A year full of challenges was highlighted by the engagements of athletes proudly wearing the colors of the ICM to help ©Ludivine Gaudry research, like Christel Chinour, who ran were also moments in which music the Paris, Moscow, and New York mara- made itself heard, with concerts such thons, but also Blandine Tissot and her as: the jazz concert of the group led by solitary race in Grenoble. The institute Jérôme Yelnik, an ICM researcher, the and its research teams also participated concert of Quatuor Quad, the concert in the “Marche Solidaire Main dans la of the soloists of the Paris Symphonic Main,” in order to increase awareness Orchestra under the direction of Cyril of ALS (amyotrophic lateral sclero- Diederich, the concert of the Groupe sis) and the work of ICM teams on this AOURA. subject. Lovers of vintage automobiles were also mobilized by a new event, the And the link between the ICM and music “Classic Festival.” does not stop there! Several musical events took place for the benefit of the Fourteen cultural events took place ICM, notably with one of its most faithful inside and outside the walls of the ICM, partners, the association Music Passion such as the projection, to thank donors, Parkinson, but also the Lions Club that of the film LUCY in the presence of Luc offered a concert/show about the life of Besson, a French film maker, producer, Barbara, in Limoges, in addition to char- scriptwriter, and Founding Member of ity events such as the one organized by the ICM, followed by a debate/discus- IDEC. sion with Prof. Yves Agid. Liz McComb, gospel diva, enabled the ICM to organize For the fourth consecutive year, the FIAC its first gala of the season, a concert supported the ICM on the occasion of at the Olympia music hall. In addition, the breakfast “Happening Créatif et de the extra-scientific lectures at the ICM Collecte” around a creation of the artist

ICM ANNUAL REPORT 2014 121 Fundraising events and the publicity campaign LIFE IN THE ICM 7

Emmanuelle Antille, photographer, prestigious automobiles of Puymirol, video and filmmaker, in collaboration organized by the Lions Club d’Agen with the teams of Stéphane Charpier of Val de Garonne, and also a bottle and Michel le Van Quyen. The aim was offered for charity by the Château du to design an operation mixing Art and Clos de Vougeot at the 53rd wine sale of Science. the Hospices de Nuits-Saint-Georges, The ICM also participated in other presided over by the actor Patrick events mixing science and culture Timsit, faithful to the ICM. Particularly such as: Conf’&Sciences organized by moved by research conducted at the the student association IndeSciences, ICM, F.P. Journe celebrated, this year, the Festival Pint of Science where one the 10 years of his association with discusses science in a bar, a concept the Institute, and continues to offer just imported from London, or yet the 30% of the profits from the sale of permanent “neuro-playful” exhibition each Centigraphe to the ICM. Since “C3RV34U” at the Cité des Sciences 2008, 525 Centifgraphe Souverains and et de l’Industrie in Paris. In addition, Centigraphe Sports have been sold the ICM organized a lecture on Jean- and contributed to the advancement of Martin Charcot by Catherine Bouchara research at the Institute. and Lionel Naccache during Brain Each of the Journées Mondiales Awareness Week that also included (Alzheimer, Parkinson, multiple scle- amusing and creative workshops. Within rosis, epilepsy, ALS, etc.) is an impor- the same context, the ICM participated tant date in the life of the ICM. The in the projection of a choreographic institute never misses an occasion to documentary “Eloge du Movement,” publish and present the numerous stud- derived from a neuroscience research ies and advances of its research. Every protocol, developed by the ICM, to evalu- trimester, the “Rendez-vous ICM” are ate the role of dance in the hospital. The the occasion for donors to meet with principal investigator is Alexandra Durr. the different members of the research Additionally, the ICM profited from community and discuss the latest auctions, including the sale of advances.

122 ICM ANNUAL REPORT 2014 THE PUBLICITY CAMPAIGN

The ICM is based on an original financial film and its simple setting, the ICM sought model combining public and private funds to address the public at large with the for faster reactivity. Support and donations fundamental question: “Is this the only are essential. The ICM therefore launched way to finance research on the brain a new campaign to attract donations and the spinal cord?” Far from a guilt- by placing the heart of the association, inducing sermon, the campaign counted medical research, at the center of its on the emotion aroused to share a very communication. positive message: by contributing to the It’s the message that the Institute wanted ICM you are giving researchers the means to transmit in order to remind the public to carry out their ambitions. of the importance of helping research on This multimedia campaign (TV, movies, nervous system disorders and accelerate web) was supplemented by poster and progress. press campaigns with same humor and With humor, the publicity film imagined wacky tone. On the model “Save our by Publicis Group, a long-term partner of planet, the ICM, with “Save our brain, help the ICM, created a surprise by addressing researchers protect it”, continues to try a broad public. On a bluesy background, to surprise readers by proposing a catchy four researchers, among their test tubes, phrase and an unexpected response in begin a clumsy strip tease to collect funds two new typographic messages of high to advance their work. With this publicity intensity.

ICM ANNUAL REPORT 2014 123

GOVERNANCE, OVERSITE, AND TRANSPARENCY

ICM ANNUAL REPORT 2014 125 Governance and oversight GOVERNANCE, OVERSITE,8 AND TRANSPARENCY

BOARD OF DIRECTORS

Gérard Saillant, President Thierry Damerval, representing the Institut Jean Todt, Vice-President National de la Sante et de la Recherche Medicale (INSERM) College of founders Bruno Riou, representating the Université Serge Weinberg Pierre et Marie Curie (UPMC) Jean Glavany Jean-François Sauvat, representating Jean-Pierre Martel the Assistance Publique-Hopitaux de Gérard Saillant Paris (APHP) Jean Todt College of the Friends College of qualified personalities of the Foundation Pierre Corvol, College de France Maurice Lévy Alain Prochiantz, Ecole Normale Superieure Lindsay Owen-Jones Elisabeth Tournier-Lasserve, Université David de Rothschild Paris Diderot Public commissioner College of full members Philippe Ritter Bernard Poulain, representing the Centre National de la Recherche Scientifique (CNRS)

126 ICM ANNUAL REPORT 2014 FOUNDING MEMBERS

Gérard Saillant, Professor of orthopaedic Olivier Lyon-Caen, Professor of Neurology, surgery and traumatology, President of ex-Director of the Pole of Nervous System the ICM Diseases of the Pitié-Salpetriere University Hospital Jean Todt, President of the FIA, Vice- President of the ICM Jean-Pierre Martel, Lawyer Max Mosley, ex-President of the FIA Yves Agid, Honorary Professor of Neurology Lindsay Owen-Jones, Honorary President and the Neurosciences of L’Oreal, Honorary President of the Luc Besson, Filmmaker Committee of the Friends of the ICM Louis Camilleri, President of Altria David de Rothschild, President of the bank Rothschild & Cie, Co-president of Jean Glavany, Former minister, Executive the Committee of the Friends of the ICM Director of the ICM Michael Schumacher, Formula 1 pilot, Maurice Lévy, President of the Board of Serge Weinberg, President of Weinberg Directors of Publicis groupe, Co-president Capital Partners, Founding Member and of the Committee of the Friends of the ICM Treasurer of the ICM

ASSOCIATION OF THE FRIENDS OF THE ICM

Lily Safra, Honorary President of the Jean-Pierre Martel, Lawyer, Founding philanthropic foundation Edmond J. Safra Member of the ICM Maurice Lévy, President of the Board of Serge Weinberg, President de Weinberg Directors of Publicis groupe, Founding Capital Partners, Founding Member and member and Co-president of the Committee Treasurer of the ICM of the Friends of the ICM David de Rothschild, President of the bank Rothschild & Cie, Founding Member and Co-president of the Committee of the Friends of the ICM