Author: "Department of Clinical and Experimental Epilepsy" - Searchworks@Jio Institute Digital Library Search Results

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1,334 results on '"Department of Clinical and Experimental Epilepsy"'

1. Seizures and Epilepsy After Stroke: Epidemiology, Biomarkers and Management

Author: Lucia Sinka, Carolina Ferreira-Atuesta, Carla Bentes, Laura Abraira, Nico Döhler, Francesco Brigo, Johan Zelano, Matthias J. Koepp, Marian Galovic, Institut Català de la Salut, [Galovic M] Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. Chalfont Centre for Epilepsy, Chalfont St Peter, UK. [Ferreira-Atuesta C] Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. Chalfont Centre for Epilepsy, Chalfont St Peter, UK. Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA. [Abraira L] Unitat d’Epilèpsia, Servei de Neurologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Sinka L] Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland. [Brigo F] Division of Neurology, 'Franz Tappeiner' Hospital, Merano, Italy, and Vall d'Hebron Barcelona Hospital Campus
Subjects: medicine.medical_specialty, Epilèpsia - Factors de risc, Review Article, enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::trastornos cerebrovasculares::accidente cerebrovascular [ENFERMEDADES], Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Epilepsy [DISEASES], técnicas de investigación::métodos epidemiológicos::estadística como asunto::probabilidad::riesgo::factores de riesgo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Epileptogenesis, Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores], 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Pharmacotherapy, Risk Factors, Seizures, Epidemiology, Humans, Medicine, Pharmacology (medical), cardiovascular diseases, 030212 general & internal medicine, Intensive care medicine, Adverse effect, Stroke, Aged, business.industry, Symptomatic seizures, medicine.disease, Malalties cerebrovasculars - Complicacions, Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Cerebrovascular Disorders::Stroke [DISEASES], Pharmacodynamics, enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::epilepsia [ENFERMEDADES], Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Geriatrics and Gerontology, business, Biomarkers, 030217 neurology & neurosurgery, Other subheadings::Other subheadings::/complications [Other subheadings]
Abstract: Convulsions; Farmacodinàmica; Electroencefalograma Convulsiones; Farmacodinámica; Electroencefalograma Seizures; Pharmacodynamics; Electroencephalogram [Galovic M] Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. Chalfont Centre for Epilepsy, Chalfont St Peter, UK. [Ferreira-Atuesta C] Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. Chalfont Centre for Epilepsy, Chalfont St Peter, UK. Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA. [Abraira L] Unitat d’Epilèpsia, Servei de Neurologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Döhler N] Specialist Clinic for Neurorehabilitation, Kliniken Beelitz, Beelitz-Heilstätten, Germany. [Sinka L] Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland. [Brigo F] Division of Neurology, “Franz Tappeiner” Hospital, Merano, Italy Open Access funding provided by Universität Zürich. No sources of funding were used to conduct this study or prepare this manuscript.
Published: 2021

2. Correction: The landscape of epilepsy-related GATOR1 variants

Author: Johannes R. Lemke, Thomas Dorn, Laura Hernandez-Hernandez, Giuseppe d'Orsi, Eveline Hagebeuk, Annapurna Poduri, Douglas R. NordliJr, Hélène Catenoix, Melanie Jennesson, Veronique Darmency, Kevin Rostasy, Thomas Becher, Laura Licchetta, Peter Uldall, Lysa Boissé Lomax, Bianca Berghuis, Ilona Krey, Gaetan Lesca, Anne de Saint Martin, Boudewijn Gunning, Anne Fabienne Lepine, Renske Oegema, Brigitte Ricard-Mousnier, Sarah Ferrand-Sorbets, Arnaud Biraben, Charles Deckers, An Sofie Schoonjans, Martin Zenker, Simona Balestrini, Inga Talvik, Julitta de Bellescize, Christopher J. Yuskaitis, Georg Dorfmüller, Erik H. Niks, Guillaume Achaz, Laurence Faivre, Pasquale Striano, Shifteh Sattar, Karen Müller-Schlüter, Sanjay M. Sisodiya, Caroline Nava, Pia Zacher, Fabrice Bartolomei, Kristin Lindstrom, Sophie Julia, Eric LeGuern, Thomas Cloppenborg, Rikke S. Møller, Antonio Gambardella, Mathilde Chipaux, Sara Baldassari, Pavel Krsek, Marie Line Jacquemont, Ilse Wegner, Christian Brandt, Barbora Benova, Valerio Conti, Gabrielle Rudolf, Floor E. Jansen, Edouard Hirsch, S. Krithika, Jamel Chelly, Katrien Stouffs, Daniëlle de Jong, Courtney Kiss, Tilman Polster, Eva H. Brilstra, Tommaso Pippucci, Markus Wolff, Cécile Marchal, Giovanni Crichiutti, Kees P.J. Braun, Paolo Tinuper, Stéphanie Baulac, Valentin Sander, Anne-Sophie Lebre, Nienke E. Verbeek, Anna Jansen, Francesca Bisulli, Fabienne Picard, Natasha E. Schoeler, Julien Thevenon, Marjan J. A. van Kempen, Guido Rubboli, Sarah Weckhuysen, Renzo Guerrini, Eleni Panagiotakaki, Meral Balci, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Universitaire de Genève, Department of Genetics [Utrecht, the Netherlands], University Medical Center [Utrecht], Children's Hospital A. Meyer, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Molecular Cell Biology, Leiden University Medical Center (LUMC), Danish Epilepsy Centre, Denmark and Aarhus University, Aarhus, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurogénétique Moléculaire et Cellulaire, Institut Naltional de la Santé et de la Recherche Médicale, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Regional Epilepsy Center, Reggio Calabria, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Département de Sociologie [université de Bourgogne], UFR de sciences humaines [Université de Bourgogne], Université de Bourgogne (UB)-Université de Bourgogne (UB), Service de Neurophysiologie Clinique (CHU Dijon), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Universitair Ziekenhuis Brussel, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon], Hospices Civils de Lyon (HCL), Institute of Human Genetics, University Hospital Magdeburg, Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), University of Southern Denmark (SDU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Universiteit Leiden-Universiteit Leiden, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Muséum national d'Histoire naturelle (MNHN)-École Pratique des Hautes Études (EPHE), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0303 health sciences, business.industry, Published Erratum, MEDLINE, medicine.disease, computer.software_genre, Spelling, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, medicine, Artificial intelligence, business, Psychology, computer, 030217 neurology & neurosurgery, Genetics (clinical), Natural language processing, 030304 developmental biology
Abstract: International audience; The original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article.
Published: 2019

3. Microbiota-gut brain axis involvement in neuropsychiatric disorders

Author: Hervé M. Blottière, Emilio Russo, Sigrid Pedersen, Francesca Ronchi, Luigi Francesco Iannone, Gaia Luongo, Federico Zara, Cinzia Ferraris, P. Mainardi, Anna Tagliabue, Alberto Preda, Gerard Clarke, Kaja Kristine Selmer, Elisa Santocchi, Stefania Provasi, Vincenzo Belcastro, Carmen Giordano, Alberto Verrotti, Pietro Baldelli, Carlo Minetti, Rita Citraro, Diego Albani, Pasquale Striano, Andrea Petretto, Paola Iannetti, Marco Carotenuto, Jakob Zimmermann, Nicola Segata, Annamaria Cattaneo, Alberto Spalice, Letizia Guiducci, Sanjay M. Sisodiya, Iannone, Luigi Francesco, Preda, Alberto, Blottière, Hervé M, Clarke, Gerard, Albani, Diego, Belcastro, Vincenzo, Carotenuto, Marco, Cattaneo, Annamaria, Citraro, Rita, Ferraris, Cinzia, Ronchi, Francesca, Luongo, Gaia, Santocchi, Elisa, Guiducci, Letizia, Baldelli, Pietro, Iannetti, Paola, Pedersen, Sigrid, Petretto, Andrea, Provasi, Stefania, Selmer, Kaja, Spalice, Alberto, Tagliabue, Anna, Verrotti, Alberto, Segata, Nicola, Zimmermann, Jakob, Minetti, Carlo, Mainardi, Paolo, Giordano, Carmen, Sisodiya, Sanjay, Zara, Federico, Russo, Emilio, Striano, Pasquale, University of Catanzaro, University of Genoa (UNIGE), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, University College Cork (UCC), IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri', Saint Anna Hospital, Partenaires INRAE, Università degli studi della Campania 'Luigi Vanvitelli', King's College, University of Pavia, University of Bern, Ordine dei Tecnologi Alimentari Campania e Lazio, Stella Maris Foundation, Institute of Clinical Physiology, National Council of Research, University of Genova, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Oslo University Hospital [Oslo], Istituto Giannina Gaslini, University of Laquila, University of Trento, Kolfarma SRL, Department of Chemistry, Materials and Chemical Engineering 'Giulio Natta' (CMIC), Politecnico di Milano [Milan] (POLIMI), Department of Clinical and Experimental Epilepsy, and UCL Institute of Neurology
Subjects: microbiota-gut brain axis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Central nervous system, Gut–brain axis, Inflammation, Bidirectional communication, digestive system, 03 medical and health sciences, fluids and secretions, 0302 clinical medicine, Ketogenic diet, inflammation, manipulating microbiota, metabolomics, neuropsychiatric disorders, Central Nervous System Diseases, medicine, microbiota-gut brain axi, Humans, Pharmacology (medical), Ketogenic diet, inflammation, manipulating microbiota, metabolomics, microbiota-gut brain axis, neuropsychiatric disorders, business.industry, General Neuroscience, Multiple sclerosis, Mental Disorders, medicine.disease, 3. Good health, 030227 psychiatry, Clinical neurology, Gastrointestinal Microbiome, stomatognathic diseases, medicine.anatomical_structure, Clinical evidence, Immunology, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, metabolomic
Abstract: International audience; Introduction: The microbiota-gut brain (MGB) axis is the bidirectional communication between the intestinal microbiota and the brain. An increasing body of preclinical and clinical evidence has revealed that the gut microbial ecosystem can affect neuropsychiatric health. However, there is still a need of further studies to elucidate the complex gene-environment interactions and the role of the MGB axis in neuropsychiatric diseases, with the aim of identifying biomarkers and new therapeutic targets, to allow early diagnosis and improving treatments. Areas covered: To review the role of MGB axis in neuropsychiatric disorders, prediction and prevention of disease through exploitation, integration, and combination of data from existing gut microbiome/microbiota projects and appropriate other International '-Omics' studies. The authors also evaluated the new technological advances to investigate and modulate, through nutritional and other interventions, the gut microbiota. Expert opinion: The clinical studies have documented an association between alterations in gut microbiota composition and/or function, whereas the preclinical studies support a role for the gut microbiota in impacting behaviors which are of relevance to psychiatry and other central nervous system (CNS) disorders. Targeting MGB axis could be an additional approach for treating CNS disorders and all conditions in which alterations of the gut microbiota are involved.
Published: 2019

4. SNARE Machinery is optimized for ultra-fast fusion

Author: Fabio Manca, Frederic Pincet, Lionel Foret, James E. Rothman, Lev Truskinovsky, Matthieu Caruel, Laboratoire de physique de l'ENS - ENS Paris (LPENS (UMR_8023)), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Mécanismes Moléculaires Membranaires, Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Physique et mécanique des milieux hétérogenes (PMMH (UMR_7636)), Université Paris Diderot - Paris 7 (UPD7)-ESPCI ParisTech-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Cell Biology [New Haven], Yale University School of Medicine-Howard Hugues Medical Institute, Department of Clinical and Experimental Epilepsy [London, UK] (Institute of Neurology), University College of London [London] (UCL), Biophysique et Neuroscience Théoriques, Laboratoire de Modélisation et Simulation Multi Echelle (MSME), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Paris-Est Marne-la-Vallée (UPEM), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Université Paris Diderot - Paris 7 (UPD7), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Université Paris Diderot - Paris 7 (UPD7)-École normale supérieure - Paris (ENS Paris), Physique et mécanique des milieux hétérogenes (UMR 7636) (PMMH), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Yale University School of Medicine-Howard Hughes Medical Institute (HHMI), Université Paris-Est Marne-la-Vallée (UPEM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Yale School of Medicine [New Haven, Connecticut] (YSM)-Howard Hughes Medical Institute (HHMI)
Subjects: 0301 basic medicine, Vesicle fusion, Zipper, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], membrane fusion, MathematicsofComputing_GENERAL, FOS: Physical sciences, Synaptic vesicle, Models, Biological, Corrections, 03 medical and health sciences, muscle contraction, 0302 clinical medicine, protein folding, Animals, Physics - Biological Physics, [PHYS.MECA.BIOM]Physics [physics]/Mechanics [physics]/Biomechanics [physics.med-ph], [PHYS.COND.CM-SM]Physics [physics]/Condensed Matter [cond-mat]/Statistical Mechanics [cond-mat.stat-mech], ComputingMilieux_MISCELLANEOUS, Physics, Millisecond, Fusion, Multidisciplinary, Cryoelectron Microscopy, Lipid bilayer fusion, Coupling (electronics), Biophysics and Computational Biology, 030104 developmental biology, PNAS Plus, neurotransmitter release, Biological Physics (physics.bio-ph), SNARE, Physical Sciences, Biophysics, Protein folding, SNARE Proteins, 030217 neurology & neurosurgery, Protein Binding
Abstract: Significance We propose a mechanistic description of fusion of a synaptic vesicle with a target membrane executed by a team of zippering SNARE complexes (SNAREpins). In the context of neurotransmitters release, this process naturally decomposes in two steps with rates that depend on the number of SNAREpins N. The first step is synchronized escape from the metastable half-zippered state, which gets exponentially more sluggish as N increases. The second step is fusion of two closely tethered membranes, which is accelerated exponentially by an increase of N. The tradeoff between these two antagonist trends results in a sharply optimal number of SNAREpins N=3−6, which ensures fusion at the physiological submillisecond timescale., SNARE proteins zipper to form complexes (SNAREpins) that power vesicle fusion with target membranes in a variety of biological processes. A single SNAREpin takes about 1 s to fuse two bilayers, yet a handful can ensure release of neurotransmitters from synaptic vesicles much faster: in a 10th of a millisecond. We propose that, similar to the case of muscle myosins, the ultrafast fusion results from cooperative action of many SNAREpins. The coupling originates from mechanical interactions induced by confining scaffolds. Each SNAREpin is known to have enough energy to overcome the fusion barrier of 25–35 kBT; however, the fusion barrier only becomes relevant when the SNAREpins are nearly completely zippered, and from this state, each SNAREpin can deliver only a small fraction of this energy as mechanical work. Therefore, they have to act cooperatively, and we show that at least three of them are needed to ensure fusion in less than a millisecond. However, to reach the prefusion state collectively, starting from the experimentally observed half-zippered metastable state, the SNAREpins have to mechanically synchronize, which takes more time as the number of SNAREpins increases. Incorporating this somewhat counterintuitive idea in a simple coarse-grained model results in the prediction that there should be an optimum number of SNAREpins for submillisecond fusion: three to six over a wide range of parameters. Interestingly, in situ cryoelectron microscope tomography has very recently shown that exactly six SNAREpins participate in the fusion of each synaptic vesicle. This number is in the range predicted by our theory.
Published: 2019

5. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author: Patrick May, Simon Girard, Merle Harrer, Dheeraj R Bobbili, Julian Schubert, Stefan Wolking, Felicitas Becker, Pamela Lachance-Touchette, Caroline Meloche, Micheline Gravel, Cristina E Niturad, Julia Knaus, Carolien De Kovel, Mohamad Toliat, Anne Polvi, Michele Iacomino, Rosa Guerrero-López, Stéphanie Baulac, Carla Marini, Holger Thiele, Janine Altmüller, Kamel Jabbari, Ann-Kathrin Ruppert, Wiktor Jurkowski, Dennis Lal, Raffaella Rusconi, Sandrine Cestèle, Benedetta Terragni, Ian D Coombs, Christopher A Reid, Pasquale Striano, Hande Caglayan, Auli Siren, Kate Everett, Rikke S Møller, Helle Hjalgrim, Hiltrud Muhle, Ingo Helbig, Wolfram S Kunz, Yvonne G Weber, Sarah Weckhuysen, Peter De Jonghe, Sanjay M Sisodiya, Rima Nabbout, Silvana Franceschetti, Antonietta Coppola, Maria S Vari, Dorothée Kasteleijn-Nolst Trenité, Betul Baykan, Ugur Ozbek, Nerses Bebek, Karl M Klein, Felix Rosenow, Dang K Nguyen, François Dubeau, Lionel Carmant, Anne Lortie, Richard Desbiens, Jean-François Clément, Cécile Cieuta-Walti, Graeme J Sills, Pauls Auce, Ben Francis, Michael R Johnson, Anthony G Marson, Bianca Berghuis, Josemir W Sander, Andreja Avbersek, Mark McCormack, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Martin Krenn, Fritz Zimprich, Sarah Peter, Marina Nikanorova, Robert Kraaij, Jeroen van Rooij, Rudi Balling, M Arfan Ikram, André G Uitterlinden, Giuliano Avanzini, Stephanie Schorge, Steven Petrou, Massimo Mantegazza, Thomas Sander, Eric LeGuern, Jose M Serratosa, Bobby P C Koeleman, Aarno Palotie, Anna-Elina Lehesjoki, Michael Nothnagel, Peter Nürnberg, Snezana Maljevic, Federico Zara, Patrick Cossette, Roland Krause, Holger Lerche, Edoardo Ferlazzo, Carlo di Bonaventura, Angela La Neve, Paolo Tinuper, Francesca Bisulli, Aglaia Vignoli, Giuseppe Capovilla, Giovanni Crichiutti, Antonio Gambardella, Vincenzo Belcastro, Amedeo Bianchi, Destina Yalçın, Gulsen Dizdarer, Kezban Arslan, Zuhal Yapıcı, Demet Kuşcu, Costin Leu, Kristin Heggeli, Joseph Willis, Sarah R Langley, Andrea Jorgensen, Prashant Srivastava, Sarah Rau, Christian Hengsbach, Anja C.M. Sonsma, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratory of Molecular Genetics of Stem Cells [University of Montreal], University of Montreal-Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), University of Tübingen, University Medical Center [Utrecht], Universita degli studi di Genova, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), A.Meyer Children's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, The Genome Analysis Centre (TGAC), Cologne Center for Genomics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Department of Neurophysiopathology, Besta Neurological Institute, University of Southern Denmark (SDU), Medical Genetics Laboratory, Children’s Hospital of Philadelphia (CHOP ), Universitätsklinikum Bonn (UKB), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituco Neurologico C. Besta, Instituto Neurologico C. Besta, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), University of Liverpool, Institute of Neurology [London], Royal College of Surgeons in Ireland (RCSI), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Medical Informatics and Statistics, Pediatric Neurology and Neuromuscular Diseases Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Hertie Institute for Clinical Brain Research [Tubingen], Regional Epilepsy Center, Reggio Calabria, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Wellcome Trust, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Università degli studi di Genova = University of Genoa (UniGe), Heart Center Leipzig, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Acibadem University Dspace, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Nice Sophia Antipolis (... - 2019) (UNS), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Medicum, Research Programme for Molecular Neurology, Research Programs Unit, Neuroscience Center, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, Epicure Consortium, EuroEPINOMICS COGIE Consortium, EpiPGX Consortium, May, Gabriella, Girard, S., Harrer, M., Bobbili, D. R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., Niturad, C. E., Knaus, J., De Kovel, C., Toliat, M., Polvi, A., Iacomino, M., Guerrero-López, R., Baulac, S., Marini, C., Thiele, H., Altmüller, J., Jabbari, K., Ruppert, A. -K., Jurkowski, W., Lal, D., Rusconi, R., Cestèle, S., Terragni, B., Coombs, I. D., Reid, C. A., Striano, P., Caglayan, H., Siren, A., Everett, K., Møller, R. S., Hjalgrim, H., Muhle, H., Helbig, I., Kunz, W. S., Weber, Y. G., Weckhuysen, S., Jonghe, P. D., Sisodiya, S. M., Nabbout, R., Franceschetti, S., Coppola, A., Vari, M. S., Kasteleijn-Nolst Trenité, D., Baykan, B., Ozbek, U., Bebek, N., Klein, K. M., Rosenow, F., Nguyen, D. K., Dubeau, F., Carmant, L., Lortie, A., Desbiens, R., Clément, J. -F., Cieuta-Walti, C., Sills, G. J., Auce, P., Francis, B., Johnson, M. R., Marson, A. G., Berghuis, B., Sander, J. W., Avbersek, A., Mccormack, M., Cavalleri, G. L., Delanty, N., Depondt, C., Krenn, M., Zimprich, F., Peter, S., Nikanorova, M., Kraaij, R., van Rooij, J., Balling, R., Ikram, M. A., Uitterlinden, A. G., Avanzini, Giulio, Schorge, S., Petrou, S., Mantegazza, M., Sander, T., Leguern, E., Serratosa, J. M., Koeleman, B. P. C., Palotie, A., Lehesjoki, A. -E., Nothnagel, M., Nürnberg, P., Maljevic, S., Zara, F., Cossette, P., Krause, R., Lerche, H., De Jonghe, P., Arfan Ikram, M., Ferlazzo, E., di Bonaventura, C., La Neve, A., Tinuper, P., Bisulli, F., Vignoli, Massimo, Capovilla, G., Crichiutti, G., Gambardella, A., Belcastro, V., Bianchi, A., Yalçın, D., Dizdarer, G., Arslan, K., Yapıcı, Z., Kuşcu, D., Leu, C., Heggeli, K., Willis, J., Langley, S. R., Jorgensen, A., Srivastava, P., Rau, S., Hengsbach, C., Sonsma, A. C. M., University of Montreal-Institute for Research in Immunology and Cancer (IRIC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], Hôpital Erasme (Bruxelles), May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicita, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Denni, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, Jonghe, Peter De, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerse, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, Françoi, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-Françoi, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Paul, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M Arfan, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thoma, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, De Jonghe, Peter, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, and Sonsma, Anja C.M.
Subjects: 0301 basic medicine, GAMMA-2-SUBUNIT, [SDV]Life Sciences [q-bio], GABRA5, Clinical Neurology, 15Q13.3 MICRODELETIONS, ABSENCE EPILEPSY, SEQUENCE DATA, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 3124 Neurology and psychiatry, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic variation, medicine, EPILEPTIC ENCEPHALOPATHIES, Exome, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetic association, Genetics, RISK, Science & Technology, FEBRILE SEIZURES, Neurology & Neurosurgery, biology, 3112 Neurosciences, 1103 Clinical Sciences, MOUSE MODEL, medicine.disease, ASSOCIATION ANALYSIS, 030104 developmental biology, DE-NOVO MUTATIONS, Cohort, biology.protein, Neurology (clinical), Human medicine, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Cohort study
Abstract: BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).
Published: 2018

6. The landscape of epilepsy-related GATOR1 variants

Author: Johannes R. Lemke, Pia Zacher, Thomas Dorn, Laura Hernandez-Hernandez, Natasha E. Schoeler, Stéphanie Baulac, Sara Baldassari, Anne de Saint Martin, Eleni Panagiotakaki, Anne Fabienne Lepine, Markus Wolff, Arnaud Biraben, Renske Oegema, Edouard Hirsch, Anna Jansen, Charles Deckers, Nienke E. Verbeek, Fabienne Picard, Georg Dorfmüller, Sarah Ferrand-Sorbets, Barbora Benova, Francesca Bisulli, Inga Talvik, Kristin Lindstrom, Tilman Polster, Douglas R. Nordli, Tommaso Pippucci, Eva H. Brilstra, Shifteh Sattar, Erik H. Niks, Marie Line Jacquemont, Kees P.J. Braun, Karen Müller-Schlüter, Sanjay M. Sisodiya, Sarah Weckhuysen, Lysa Boissé Lomax, Sophie Julia, Brigitte Ricard-Mousnier, Mathilde Chipaux, Laura Licchetta, Gaetan Lesca, Bianca Berghuis, S. Krithika, Jamel Chelly, Renzo Guerrini, Hélène Catenoix, Annapurna Poduri, Melanie Jennesson, Pasquale Striano, Rikke S. Møller, Antonio Gambardella, Guillaume Achaz, Peter Uldall, Fabrice Bartolomei, Giuseppe d'Orsi, Laurence Faivre, Floor E. Jansen, An Sofie Schoonjans, Kevin Rostasy, Thomas Becher, Pavel Krsek, Julien Thevenon, Marjan J. A. van Kempen, Guido Rubboli, Cécile Marchal, Meral Balci, Boudewijn Gunning, Ilona Krey, Julitta de Bellescize, Veronique Darmency, Christopher J. Yuskaitis, Daniëlle de Jong, Giovanni Crichiutti, Paolo Tinuper, Katrien Stouffs, Valentin Sander, Anne-Sophie Lebre, Thomas Cloppenborg, Valerio Conti, Gabrielle Rudolf, Courtney Kiss, Eveline Hagebeuk, Caroline Nava, Eric LeGuern, Ilse Wegner, Christian Brandt, Martin Zenker, Simona Balestrini, Picard, Fabienne, Baldassari S., Picard F., Verbeek N.E., van Kempen M., Brilstra E.H., Lesca G., Conti V., Guerrini R., Bisulli F., Licchetta L., Pippucci T., Tinuper P., Hirsch E., de Saint Martin A., Chelly J., Rudolf G., Chipaux M., Ferrand-Sorbets S., Dorfmuller G., Sisodiya S., Balestrini S., Schoeler N., Hernandez-Hernandez L., Krithika S., Oegema R., Hagebeuk E., Gunning B., Deckers C., Berghuis B., Wegner I., Niks E., Jansen F.E., Braun K., de Jong D., Rubboli G., Talvik I., Sander V., Uldall P., Jacquemont M.-L., Nava C., Leguern E., Julia S., Gambardella A., d'Orsi G., Crichiutti G., Faivre L., Darmency V., Benova B., Krsek P., Biraben A., Lebre A.-S., Jennesson M., Sattar S., Marchal C., Nordli D.R., Lindstrom K., Striano P., Lomax L.B., Kiss C., Bartolomei F., Lepine A.F., Schoonjans A.-S., Stouffs K., Jansen A., Panagiotakaki E., Ricard-Mousnier B., Thevenon J., de Bellescize J., Catenoix H., Dorn T., Zenker M., Muller-Schluter K., Brandt C., Krey I., Polster T., Wolff M., Balci M., Rostasy K., Achaz G., Zacher P., Becher T., Cloppenborg T., Yuskaitis C.J., Weckhuysen S., Poduri A., Lemke J.R., Moller R.S., Baulac S., Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Genetics [Utrecht, the Netherlands], University Medical Center [Utrecht], Service de Génétique [HCL Groupement Hospitalier Est], Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Children's Hospital A. Meyer, Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Academic Center for Epileptology Kempenhaeghe & Maastricht UMC+ [Heeze], Danish Epilepsy Centre, Denmark and Aarhus University, Aarhus, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Université de Bourgogne (UB), Service de Neurophysiologie Clinique (CHU Dijon), CHU Pontchaillou [Rennes], Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon], Hospices Civils de Lyon (HCL), Institute of Human Genetics, University Hospital Magdeburg, Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupement hospitalier Lyon-Est, Centre de recherche en neurosciences de Lyon (CRNL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]
Subjects: Male, 0301 basic medicine, Proband, DEPDC5, SUDEP, 030105 genetics & heredity, Bioinformatics, Loss of Function Mutation/genetics, Epilepsy, INDEL Mutation, Loss of Function Mutation, mTORC1 pathway, Genetics(clinical), Child, Genetics (clinical), Multiprotein Complexes/genetics, Brugada Syndrome, DNA Copy Number Variation, Brugada syndrome, INDEL Mutation/genetics, GTPase-Activating Proteins, NPRL3, Seizure, Phenotype, Pedigree, 3. Good health, Brugada Syndrome/genetics, Child, Preschool, Female, Human, Signal Transduction, DNA Copy Number Variations, Adolescent, Seizures/complications, Mechanistic Target of Rapamycin Complex 1/genetics, DNA Copy Number Variations/genetics, Mechanistic Target of Rapamycin Complex 1, Tumor Suppressor Proteins/genetics, Article, Focal cortical dysplasia, 03 medical and health sciences, Seizures, GTPase-Activating Proteins/genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic focal epilepsy, Epilepsy/complications, Repressor Proteins/genetics, business.industry, GTPase-Activating Protein, Tumor Suppressor Proteins, Infant, Newborn, Correction, Infant, Repressor Protein, Cortical dysplasia, medicine.disease, ddc:616.8, Repressor Proteins, 030104 developmental biology, Frontal lobe seizures, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Multiprotein Complexes, Multiprotein Complexe, Signal Transduction/genetics, Human medicine, business
Abstract: Purpose:\ud \ud To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway.\ud \ud Methods:\ud \ud We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.\ud \ud Results:\ud \ud The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign.\ud \ud Conclusion:\ud \ud Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.
Published: 2018

7. Simulated field maps for susceptibility artefact correction in interventional MRI

Author: John S. Duncan, John S. Thornton, M. Jorge Cardoso, Mark White, Laura Mancini, Tarek A. Yousry, Danail Stoyanov, Gavin P. Winston, Pankaj Daga, Andrew W. McEvoy, Ninon Burgos, Martin Kochan, Sebastien Ourselin, Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Istituto Superiore di Sanità, Department of Environmental and Primary Prevention, Istituto Superiore di Sanità, 00161 Rome, University College London Hospitals (UCLH), Epilepsy Society, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Laser Radars Laboratory [Sofia], Bulgarian Academy of Sciences (BAS), and UCL Institute of Neurology, Queen Square, London
Subjects: Nerve fibre, Field (physics), Computer science, Interventional magnetic resonance imaging, Neurosurgery, Biomedical Engineering, Health Informatics, Magnetic Resonance Imaging, Interventional, Multimodal Imaging, Intraoperative MRI, Automation, Magnetics, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Image Processing, Computer-Assisted, Humans, Computer Simulation, Radiology, Nuclear Medicine and imaging, Computer vision, Segmentation, Mri scan, Titanium, Epilepsy, Models, Statistical, business.industry, Orientation (computer vision), Brain, Reproducibility of Results, General Medicine, Real-time MRI, Computer Graphics and Computer-Aided Design, Temporal Lobe, Computer Science Applications, Diffusion Magnetic Resonance Imaging, Surgery, Computer-Assisted, Surgery, Computer Vision and Pattern Recognition, Artificial intelligence, Artifacts, Tomography, X-Ray Computed, Nuclear medicine, business, Algorithms
Abstract: 00004; International audience; PurposeIntraoperative MRI (iMRI) is a powerful modality for acquiring images of the brain to facilitate precise image-guided neurosurgery. Diffusion-weighted MRI (DW-MRI) provides critical information about location, orientation and structure of nerve fibre tracts, but suffers from the “susceptibility artefact” stemming from magnetic field perturbations due to the step change in magnetic susceptibility at air–tissue boundaries in the head. An existing approach to correcting the artefact is to acquire a field map by means of an additional MRI scan. However, to recover true field maps from the acquired field maps near air–tissue boundaries is challenging, and acquired field maps are unavailable in historical MRI data sets. This paper reports a detailed account of our method to simulate field maps from structural MRI scans that was first presented at IPCAI 2014 and provides a thorough experimental and analysis section to quantitatively validate our technique.MethodsWe perform automatic air–tissue segmentation of intraoperative MRI scans, feed the segmentation into a field map simulation step and apply the acquired and the simulated field maps to correct DW-MRI data sets.ResultsWe report results for 12 patient data sets acquired during anterior temporal lobe resection surgery for the surgical management of focal epilepsy. We find a close agreement between acquired and simulated field maps and observe a statistically significant reduction in the susceptibility artefact in DW-MRI data sets corrected using simulated field maps in the vicinity of the resection. The artefact reduction obtained using acquired field maps remains better than that using the simulated field maps in all evaluated regions of the brain.ConclusionsThe proposed simulated field maps facilitate susceptibility artefact reduction near the resection. Accurate air–tissue segmentation is key to achieving accurate simulation. The proposed simulation approach is adaptable to different iMRI and neurosurgical applications.
Published: 2015

8. ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide

Author: Thompson, Paul M., Dennis, Emily L., Gutman, Boris A., Hibar, Derrek P., Jahanshad, Neda, Kelly, Sinead, Stein, Jason L., Whelan, Christopher D., Andreassen, Ole A., Arias-Vasquez, Alejandro, Bearden, Carrie E., Boedhoe, Premika S., van den Heuvel, Odile L., Veltman, Dick J., Brouwer, Rachel M., de Reus, Marcel A., Pol, Hilleke E.Hulshoff, van den Heuvel, Martijn P., Buckner, Randy L., Buitelaar, Jan K., Fisher, Simon E., Francks, Clyde, Franke, Barbara, Hoogman, Martine, van Rooij, Daan, Bulayeva, Kazima B., Cannon, Dara M., McDonald, Colm, Cohen, Ronald A., Conrod, Patricia J., Dale, Anders M., Holland, Dominic, Deary, Ian J., Wardlaw, Joanna M., Desrivieres, Sylvane, Schumann, Gunter, Dima, Danai, Frangou, Sophia, Donohoe, Gary, Guadalupe, Tulio, Fouche, Jean Paul, Stein, Dan J., Ganjgahi, Habib, Garavan, Hugh, Glahn, David C., Grabe, Hans J., Hashimoto, Ryota, Hosten, Norbert, Kochunov, Peter, Kremen, William S., Lee, Phil H., Mackey, Scott, Mazoyer, Bernard, Martin, Nicholas G., Medland, Sarah E., Morey, Rajendra A., Nichols, Thomas E., Paus, Tomas, Pausova, Zdenka, Shen, Li, Sisodiya, Sanjay M., Smit, Dirk J.A., Smoller, Jordan W., Toro, Roberto, Turner, Jessica A., Schmaal, Lianne, van Erp, Theo G.M., Walter, Henrik, Wang, Yalin, Wright, Margaret J., Ye, Jieping, Anatomy and neurosciences, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Psychiatry, University of Southern California (USC), Division of Mental Health and Addiction, Oslo University Hospital [Oslo], KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Department of Psychiatry, Donders Centre for Neuroscience, Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen], Department of Anatomy & Neurosciences, VU University Medical Center, Amsterdam, The Netherlands, Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht 3584 CX, The Netherlands, Department of Psychiatry [Boston], Massachusetts General Hospital [Boston], Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud university [Nijmegen]-Radboud university [Nijmegen], N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), University of Florida [Gainesville], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of California [San Diego] (UC San Diego), University of California, University of Edinburgh, Department of Hematology, 'Ion Chiricuta' Cancer Institute, Trinity College Dublin-St. James's Hospital, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa, Language and Genetics Department [Nijmegen], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Shahid Beheshti Medical University, University of Vermont [Burlington], Dpt of Psychiatry [New Haven], Yale University School of Medicine, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, International Max Planck Research School for Language Sciences (IMPRS ), Department of Mathematics [UCLA], University of California [Los Angeles] (UCLA), University of California-University of California, Laboratory of Neuro Imaging [Los Angeles] (LONI), Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University [Osaka], David Geffen School of Medicine [Los Angeles], University Medical Center [Utrecht], Greifswald University Hospital, MetaCase [Jyväskylä], University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, University of Maryland System, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Psychiatry, University of Vermont, Burlington 05401, VT, USA, Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Department of Life Sciences, Imperial College London, Queensland Institute of Medical Research, Duke University [Durham], Warwick Manufacturing Group [Coventry] (WMG), University of Warwick [Coventry], Department of Statistics [Warwick], McConnell Brain Imaging Centre (MNI), Montreal Neurological Institute and Hospital, McGill University-McGill University, Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada, VU University Medical Center [Amsterdam], Göttingen Zentrum Geowissenschaften, Georg-August-Universität Göttingen, Indiana University School of Medicine, Indiana University System, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Shell (Netherlands), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), University of York [York, UK], Department of Psychiatry and Human Behavior [Irvine], University of California [Irvine] (UCI), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Berlin School of Mind and Brain [Berlin], Humboldt Universität zu Berlin, Arizona State University [Tempe] (ASU), Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia, Chinese Center for Disease Control and Prevention, Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen], University of Florida [Gainesville] (UF), McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Georg-August-University [Göttingen], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Humboldt-Universität zu Berlin, University of Maryland School of Medicine, University of Maryland System-University of Maryland System-University of Maryland [Baltimore County] (UMBC), Amsterdam Neuroscience - Brain Imaging, Biological Psychology, Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen], Radboud University [Nijmegen]-Radboud University [Nijmegen], University of California (UC), Radboud University [Nijmegen], Yale School of Medicine [New Haven, Connecticut] (YSM), University of California (UC)-University of California (UC), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Georg-August-University = Georg-August-Universität Göttingen, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), University of California [Irvine] (UC Irvine), Humboldt University Of Berlin, and Université de Montréal. Faculté de médecine. Département de psychiatrie et d'addictologie
Subjects: 0301 basic medicine, Neuroinformatics, Candidate gene, endocrine system, Cognitive Neuroscience, Brain Structure and Function, BF, Genome-wide association study, Disease, Affect (psychology), Article, 150 000 MR Techniques in Brain Function, 03 medical and health sciences, 0302 clinical medicine, SDG 17 - Partnerships for the Goals, Neuroimaging, cortical surface-area, medicine, Journal Article, Humans, Multicenter Studies as Topic, alzheimers-disease, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Depression (differential diagnoses), Brain Diseases, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], white-matter, Mental Disorders, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, heritability analysis, susceptibility loci, 3. Good health, 030104 developmental biology, Neurology, Evolutionary biology, Schizophrenia, 22q11.2 deletion syndrome, Research Programm of Donders Centre for Neuroscience, genome-wide association, chronic-schizophrenia, genetic associations, Psychology, candidate genes, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 165964pub.pdf (Publisher’s version ) (Open Access) In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) – a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date – of schizophrenia and major depression – ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others11 Abbreviations: ADNI, Alzheimer's Disease Neuroimaging Initiative (http://www.adni-info.org); CHARGE, the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (http://www.chargeconsortium.com); IMAGEN, IMAging GENetics Consortium (http://www.imagen-europe.com). , ENIGMA's genomic screens – now numbering over 30,000 MRI scans – have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants – and genetic variants in general – may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures – from tens of thousands of people – that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.
Published: 2017

9. Novel genetic loci underlying human intracranial volume identified through genome-wide association

Author: G. Bruce Pike, Marcel P. Zwiers, Andreas Meyer-Lindenberg, Jeroen van der Grond, Randy L. Gollub, Karen A. Mather, Andrew J. Schork, Vidar M. Steen, Marc M. Bohlken, Nhat Trung Doan, Derek W. Morris, John B.J. Kwok, Emma J. Rose, Johanna Hass, Andrew Simmons, Tian Ge, Reinhold Schmidt, Micael Andersson, Ian J. Deary, Christopher Chen, Derrek P. Hibar, Simon E. Fisher, Lucija Abramovic, Marcella Rietschel, Edith Hofer, Simon Lovestone, Clyde Francks, Christopher R.K. Ching, Srdjan Djurovic, Lachlan T. Strike, Lorna M. Lopez, Rene L. Olvera, Owen Carmichael, M. Arfan Ikram, Andre F. Marquand, Christine Macare, W.T. Longstreth, Philippe Amouyel, Aaron L. Goldman, Wolfgang Hoffmann, Philip L. De Jager, David C. Liewald, Harald H H Göring, Aad van der Lugt, David Ames, Neeltje E.M. van Haren, Lars Nyberg, Nina Romanczuk-Seiferth, Lukas Pirpamer, Stefan Ehrlich, Alexa S. Beiser, Lianne Schmaal, Hilkka Soininen, Mark Jenkinson, Kazima B. Bulayeva, Anderson M. Winkler, Mike A. Nalls, Diana Tordesillas-Gutiérrez, Martine Hoogman, Lars T. Westlye, Loes M. Olde Loohuis, Andrew Singleton, Gabriel Cuellar-Partida, Randy L. Buckner, Dorret I. Boomsma, Dena G. Hernandez, Steven G. Potkin, Sudha Seshadri, Bertram Müller-Myhsok, D. Hoehn, Gareth E. Davies, Chantal Depondt, Henrik Walter, Michael E. Weale, Deborah Janowitz, Susanne Erk, Iryna O. Fedko, Daniel R. Weinberger, Nic J A van der Wee, Jean-Luc Martinot, Jessica A. Turner, Marieke Klein, Sandra Barral, Sebastian Mohnke, Albert Hofman, Ingrid Melle, Saud Alhusaini, Vincent Chouraki, Stephen M. Lawrie, Mark E. Bastin, Juan C. Troncoso, Jean Shin, Wiro J. Niessen, Diane M. Becker, Laura Almasy, Anders M. Dale, Benjamin S. Aribisala, Dennis van 't Ent, Marco P. Boks, M. Mallar Chakravarty, Paul M. Thompson, David Reese McKay, Michael Griswold, John Blangero, Narelle K. Hansell, Eco J. C. de Geus, Paul A. Nyquist, Susana Muñoz Maniega, Sampath Arepalli, Tatjana Rundek, Dan L. Longo, Anton J. M. de Craen, Rebekah McWhirter, Nazanin Mirza-Schreiber, Henning Tiemeier, Girma Woldehawariat, Sven Cichon, Irene Pappa, Amelia A. Assareh, Sudheer Giddaluru, Pieter J. Hoekstra, Hieab H.H. Adams, Hilleke E. Hulshoff Pol, Grant W. Montgomery, Roel A. Ophoff, Markus M. Nöthen, Sara Pudas, Sigurdur Sigurdsson, Arthur W. Toga, Tien Yin Wong, Massimo Pandolfo, Corina U. Greven, Esther Walton, Tianye Jia, David J. Stott, Gunter Schumann, Marie-José van Tol, Dalia Kasperaviciute, Thomas Wolfers, Henry Völzke, Ian Ford, Shannon L. Risacher, Jessika E. Sussmann, Nicholas G. Martin, Wei Wen, Daniah Trabzuni, Iwona Kłoszewska, Kwangsik Nho, Gianpiero L. Cavalleri, Adam M. Brickman, Sungeun Kim, Andreas Heinz, Ralph L. Sacco, Neda Jahanshad, Velandai Srikanth, Elena Shumskaya, Susan H. Blanton, Katharina Wittfeld, Badri N. Vardarajan, Joshua C. Bis, Joanne E. Curran, Helena Schmidt, Peter T. Fox, Clifford R. Jack, Jason L. Stein, Laura M. E. Blanken, Thomas Espeseth, Dick J. Veltman, Sebastian Guelfi, Margaret J. Wright, Norman Delanty, Michael Czisch, Martina Papmeyer, Oscar L. Lopez, Marjolein M. J. Van Donkelaar, Bruce M. Psaty, Jan K. Buitelaar, Sven J. van der Lee, David A. Bennett, Beng-Choon Ho, Oliver Martinez, Wiepke Cahn, Li Shen, J. Wouter Jukema, Janita Bralten, Peter Kochunov, Greig I. Zubicaray, Marcel P. van der Brug, Ching-Yu Cheng, Philipp G. Sämann, Stella Trompet, Roberto Roiz-Santiañez, David C. Glahn, Allissa Dillman, Venkata S. Mattay, Dara M. Cannon, Michael W. Weiner, Christopher D. Whelan, Alexander Teumer, Sylvane Desrivières, Ole A. Andreassen, Thomas E. Nichols, Manuel Mattheisen, Matthias Nauck, René S. Kahn, Albert V. Smith, Colin Smith, Vilmundur Gudnason, Denis A. Evans, Anouk den Braber, Katie L. McMahon, Han G. Brunner, Florian Holsboer, Yuri Milaneschi, Andrew J. Saykin, Jiemin Liao, Vince D. Calhoun, Neelum T. Aggarwal, Dennis van der Meer, Hans J. Grabe, Anita L. DeStefano, Claudia L. Satizabal, Alan B. Zonderman, Alex P. Zijdenbos, Tulio Guadalupe, Ingrid Agartz, Jordan W. Smoller, Allison C. Nugent, Alejandro Arias-Vasquez, Masashi Ikeda, Avram J. Holmes, Brenda W.J.H. Penninx, John Hardy, Herve Lemaitre, Charles DeCarli, Patrizia Mecocci, Catharina A. Hartman, Tomas Axelsson, Oliver Grimm, Irina Filippi, Wayne C. Drevets, Hans van Bokhoven, Miguel E. Rentería, Aiden Corvin, Ryota Kanai, Kristel R. van Eijk, Andrew M. McIntosh, Jouke-Jan Hottenga, Roberto Toro, Lavinia Athanasiu, Joanna M. Wardlaw, Thomas H. Mosley, Mina Ryten, Meike W. Vernooij, Michelle Luciano, Joshua L. Roffman, Rebecca F. Gottesman, Dhananjay Vaidya, Ryota Hashimoto, Mar Matarin, Adaikalavan Ramasamy, Jerome I. Rotter, Ryan L. Muetzel, Konstantinos Arfanakis, Theo G.M. van Erp, Ganesh Chauhan, Xinmin Liu, Tomáš Paus, Emma Sprooten, Christiane Wolf, David S. Knopman, Manon Bernard, Zdenka Pausova, Bryan J. Traynor, Maria C. Valdés Hernández, Robert C. Green, Russell Thomson, Ravi Duggirala, Lisa R. Yanek, Luigi Ferrucci, Bing Xu, Thomas D. Dyer, Thomas H. Wassink, Eric Westman, Jennifer S. Richards, Phil H. Lee, Benno Pütz, Mark R. Cookson, Benedicto Crespo-Facorro, Natalie A. Royle, Bernd Kraemer, Katrin Hegenscheid, Francis J. McMahon, Tatiana Foroud, M. Kamran Ikram, Myriam Fornage, Nanda Rommelse, Saima Hilal, Perminder S. Sachdev, Qiang Chen, Najaf Amin, Lenore J. Launer, Norbert Hosten, Guillén Fernández, Simone Reppermund, Ashley Beecham, Dirk J. Heslenfeld, Masaki Fukunaga, Cornelia M. van Duijn, Clinton B. Wright, Erik G. Jönsson, Sanjay M. Sisodiya, Oliver Gruber, Christophe Tzourio, André G. Uitterlinden, Robert Johnson, Jaap Oosterlaan, Bernard Mazoyer, H. Ronald Zielke, Stephanie Le Hellard, Jingyun Yang, Georg Homuth, Stéphanie Debette, Nicola J. Armstrong, Sarah E. Medland, Henry Brodaty, Beverly G Windham, Gary Donohoe, Rachel M. Brouwer, James T. Becker, Kumar B. Rajan, Daan van Rooij, Thomas W. Mühleisen, Kazutaka Ohi, Peter R. Schofield, Tonya White, Barbara Franke, Unn K. Haukvik, Debra A. Fleischman, J. Raphael Gibbs, Colm McDonald, Anbupalam Thalamuthu, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Keck School of Medicine [Los Angeles], University of Southern California (USC), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Johns Hopkins University (JHU), QIMR Berghofer Medical Research Institute, Leiden University Medical Center (LUMC), Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Miami Leonard M. Miller School of Medicine (UMMSM), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Greifswald University Hospital, Department of Neurology and Neurosurgery [Montreal], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Royal College of Surgeons in Ireland (RCSI), Umeå University, Illinois Institute of Technology (IIT), Rush University Medical Center [Chicago], University of Edinburgh, Lagos State University (LASU), University of New South Wales [Sydney] (UNSW), Murdoch University, University of Oslo (UiO), Uppsala University, Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Toronto, University of Washington [Seattle], Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Columbia University Medical Center (CUMC), Columbia University [New York], Pennington Biomedical Research Center, Louisiana State University (LSU), McGill University = Université McGill [Montréal, Canada], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lieber Institute for Brain Development [Baltimore] (LIBD), University of California [Los Angeles] (UCLA), University of California, Vrije Universiteit Amsterdam [Amsterdam] (VU), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Massachusetts General Hospital [Boston], Neuroimagerie en psychiatrie (U1000), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Maison de Solenn [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Bergen (UiB), Haukeland University Hospital, Johns Hopkins University School of Medicine [Baltimore], Universität Heidelberg [Heidelberg], University of Mississippi Medical Center (UMMC), International Max Planck Research School for Language Sciences (IMPRS ), Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Language and Genetics Department [Nijmegen], National University of Singapore (NUS), Medical University Graz, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Yale University [New Haven], University College of London [London] (UCL), Imperial College London, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Medstar Research Institute, Clinical And Experimental Epilepsy, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Institute of Human Genetics, University of Bonn, Department of Genomics, Life and Brain Center, Groupe d'imagerie neurofonctionnelle (GIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Dpt of Psychiatry [New Haven], Yale University School of Medicine, Department of Psychiatry, VU University Medical Center [Amsterdam], Department of Psychology [Minneapolis], University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Indiana University System, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Statistical Genetics Group, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), INSERM, Neuroepidemiology U708, Bordeaux, France, Department of Cognitive Sciences [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Department of Neurosciences [San Diego], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Queensland Institute of Medical Research, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Genetics, King Faisal Specialist Hospital and Research Centre, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Depts of Radiology, University of Twente [Netherlands], Department of Psychiatry and Human Behavior [Irvine], University of California [Irvine] (UCI), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud university [Nijmegen]-Radboud university [Nijmegen], Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Deutsche Bundesbank, National Institutes of Health [Bethesda] (NIH), General Internal Medicine, Johns Hopkins School of Medicine, Biospective [Montréal], KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Department of Clinical Genetics, Department of Medical Parasitology and Mycology, School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-Tehran University of Medical Siences, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), The University of Texas Health Science Center at Houston (UTHealth), Texas Biomedical Research Institute [San Antonio, TX], 849 Department of Human Genetics, Dementia Collaborative Research Centre, Centre for Healthy Brain Ageing, Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht 3584 CX, The Netherlands, Université de Lausanne (UNIL), Department of Psychiatry [Boston], N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Icahn School of Medicine at Mount Sinai [New York] (MSSM), The Mind Research Network, Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Division of Molecular and Cellular Therapeutics, Metacohorts Consortium, Division of Medical Genetics, University of Basel (Unibas), Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Trinity College Dublin-St. James's Hospital, Department of Materials Science & Metallurgy, University of Cambridge [UK] (CAM), Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], VU University Amsterdam, Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), School of Psychology, University of Queensland, Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Molecular and Cellular Therapeutics, Department of Neurology, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Laboratory of Neurogenetics, Department of Genomics, Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Department of Radiology, Mayo Clinic, Department of Medical and Molecular Genetics, South Texas Veterans Health Care System, San Antonio, Texas 78229, USA, Department of Physics, Okayama University, Okayama University, National Institute of Aging, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Public Health Genomics Unit, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Department of Mathematics, University of Colorado, University of Colorado [Boulder], Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Department of Molecular Neurosciences, Institute of Neurology, UCL, Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University [Osaka], Department of Psychiatry, University of Iowa, University of Iowa [Iowa City], University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Tohoku University [Sendai], Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Centre for Allergy Research, Karolinska Institutet [Stockholm], Interuniversity Cardiology Institute Netherlands, Institute of Cognitive Neuroscience, School of Psychology, University of Sussex, Brighton BN1 9QH, UK, University of Sussex, Medical University of Łódź (MUL), Mayo Clinic [Rochester], University of Maryland School of Medicine, University of Maryland System-University of Maryland System-University of Maryland [Baltimore County] (UMBC), University of Maryland System, Department of Civil and Structural Engineering, The Hong Kong Polytechnic University [Hong Kong] (POLYU)-The Hong Kong Polytechnic University [Hong Kong] (POLYU), Université de Cergy Pontoise (UCP), Université Paris-Seine, Lymphocyte Cell Biology Unit, Laboratory of Genetics, Laboratoire de Statistique Théorique et Appliquée (LSTA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Psychiatry Institute, Department of Health and Human Services, Department of Life Sciences, Mathematical Sciences Institute (MSI), Australian National University (ANU), Centre for Advanced Imaging, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia (UNIPG), Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Medical Faculty [Mannheim], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, Université de Toulon - UFR Lettres et Sciences Humaines (UTLN UFR LSH), Université de Toulon (UTLN), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Institute of Clinical Chemistry and Laboratory Medicine, Warwick Manufacturing Group [Coventry] (WMG), University of Warwick [Coventry], Department of Statistics [Warwick], Delft University of Technology (TU Delft), Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, McConnell Brain Imaging Centre (MNI), Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, Group Health Research Institute, Group Health Cooperative, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Cedars-Sinai Medical Center, Centre for Healthy Brain Ageing [Sydney], The University of Sydney, Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Department of Medical Biochemistry and Microbiology, Department of Clinical and Experimental Epilepsy, Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Monash University [Melbourne], Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia, University of Tasmania [Hobart, Australia] (UTAS), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, Department of Epidemiology, Laboratory of Neuro Imaging [Los Angeles] (LONI), University of York [York, UK], Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], Departments of Radiology and of Epidemiology [Rotterdam], Psychiatry and Leiden Institute for Brain and Cognition, Department of Neurology [Rotterdam], Institute for Community Medicine, Berlin School of Mind and Brain [Berlin], Humboldt-Universität zu Berlin, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Centre for Population Health Sciences, Department of Physics [Hong Kong University of Science and Technology], Hong Kong University of Science and Technology (HKUST), Department of Neurobiology, Care Sciences and Society, Research Laboratory for Archaeology & the History of Art, Singapore Eye Research Institute, Singapore National Eye Centre, School of Life Sciences, Arizona State University [Tempe] (ASU), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], University of Missouri [Columbia] (Mizzou), University of Missouri System, Göttingen Zentrum Geowissenschaften, Georg-August-University [Göttingen], Human Genetics Center, Psychiatry, EMGO - Mental health, Amsterdam Neuroscience - Complex Trait Genetics, Anatomy and neurosciences, Klinische Genetica, MUMC+: DA Klinische Genetica (5), RS: FHML non-thematic output, RS: GROW - School for Oncology and Reproduction, RS: GROW - R4 - Reproductive and Perinatal Medicine, Genetica & Celbiologie, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Universidad de Cantabria, Universiteit Leiden, Radboud University [Nijmegen], University of California (UC), Universität Heidelberg [Heidelberg] = Heidelberg University, Universität Bonn = University of Bonn, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Yale School of Medicine [New Haven, Connecticut] (YSM), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), University of California (UC)-University of California (UC), Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), King Faisal Specialist Hospital and Research Centre (KFSH & RC), Universiteit Leiden-Universiteit Leiden, University of Twente, University of California [Irvine] (UC Irvine), Radboud University [Nijmegen]-Radboud University [Nijmegen], Centre épigénétique et destin cellulaire (EDC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Università degli Studi di Perugia = University of Perugia (UNIPG), University Hospital Mannheim | Universitätsmedizin Mannheim, Universität Leipzig-Universität Leipzig, University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, Harvard University-Massachusetts Institute of Technology (MIT), University of Eastern Finland, Humboldt University Of Berlin, Georg-August-University = Georg-August-Universität Göttingen, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Epidemiology, Child and Adolescent Psychiatry / Psychology, Ophthalmology, Radiology & Nuclear Medicine, Internal Medicine, Neurosciences, Obstetrics & Gynecology, Neurology, EMGO+ - Mental Health, Biological Psychology, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), McGill University-McGill University, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), McGill University, Technische Universität Dresden (TUD), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], University of Bergen (UIB), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Minnesota [Twin Cities], Karakter Child and Adolescent Psychiatry University Center Nijmegen, Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Okayama University [Okayama], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Massachusetts Institute of Technology (MIT)-Harvard University [Cambridge], University of Tasmania (UTAS), Humboldt Universität zu Berlin, Department of Physics [Kowloon], University of Missouri [Columbia], Georg-August-Universität Göttingen, and the Alzheimer's Disease Neuroimaging Initiative, EPIGEN, IMAGEN, SYS
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Genome-wide association study, Disease, methods [Genome-Wide Association Study], Genome-wide association studies, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Cognition, PARKINSONS-DISEASE, pathology [Brain], genetics [Parkinson Disease], 610 Medicine & health, General Neuroscience, growth & development [Brain], physiology [Cognition], 220 Statistical Imaging Neuroscience, COMMON VARIANTS, Brain, Parkinson Disease, Phenotype, 17Q21.31 MICRODELETION, IGF-I, genetics [Oncogene Protein v-akt], Oncogene Protein v-akt, ALZHEIMERS-DISEASE, HEAD CIRCUMFERENCE, Brain size, genetics [Polymorphism, Single Nucleotide], Medical genetics, GROWTH, Neuroinformatics, medicine.medical_specialty, Neuroscience(all), European Continental Ancestry Group, genetics [Genetic Loci], Biology, Genetic correlation, Polymorphism, Single Nucleotide, 150 000 MR Techniques in Brain Function, Article, White People, 03 medical and health sciences, Image processing, SDG 3 - Good Health and Well-being, ddc:570, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Gene, METAANALYSIS, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Height, [SCCO.NEUR]Cognitive science/Neuroscience, CONSORTIUM, Development of the nervous system, 1702 Cognitive Science, 030104 developmental biology, Genetic Loci, Human genome, BRAIN SIZE, 1109 Neurosciences, genetics [Phosphatidylinositol 3-Kinases], Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 165723pub.pdf (Publisher’s version ) (Closed access) Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rhogenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
Published: 2016

10. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Author: Conceição, Bettencourt, Davina, Hensman-Moss, Michael, Flower, Sarah, Wiethoff, Alexis, Brice, Cyril, Goizet, Giovanni, Stevanin, Georgios, Koutsis, Georgia, Karadima, Marios, Panas, Petra, Yescas-Gómez, Lizbeth Esmeralda, García-Velázquez, María Elisa, Alonso-Vilatela, Manuela, Lima, Mafalda, Raposo, Bryan, Traynor, Mary, Sweeney, Nicholas, Wood, Paola, Giunti, Alexandra, Durr, Peter, Holmans, Henry, Houlden, Sarah J, Tabrizi, Lesley, Jones, Department of Molecular Neuroscience, University College of London [London] (UCL)-Institute of Neurology, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Department of Neurodegenerative Diseases, Institute of Neurology, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme, Université de Bordeaux (UB), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), University of Athens Medical School [Athens], National Institute of Neurology and Neurosurgery, University of the Azores, Universidade do Porto = University of Porto, BMC –Institute for Molecular and Cell Biology (ICBAS), National Institute of Aging, National Hospital for Neurology & Neurosurgery, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], HAL-UPMC, Gestionnaire, Hertie Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Universidade do Porto, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and École Pratique des Hautes Études (EPHE)
Subjects: Endodeoxyribonucleases, DNA Repair, Multifunctional Enzymes, Polymorphism, Single Nucleotide, Exodeoxyribonucleases, Huntington Disease, Mutation, Humans, Spinocerebellar Ataxias, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Age of Onset, Trinucleotide Repeat Expansion, Research Articles, Genome-Wide Association Study, Mismatch Repair Endonuclease PMS2, Research Article
Abstract: The SPATAX Network; International audience; ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome-wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.MethodsWe assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single-nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.ResultsIn the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS.InterpretationWe show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016
Published: 2016

11. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy

Author: Mignot, C., von Stulpnage, C., Nava, C., Ville, D., Sanlaville, D., Lesca, G., Rastetter, A., Gachet, B., Marie, Y., Korenke, G. C., Borggraefe, I., Hoffmann-Zacharska, D., Szczepanik, E., Rudzka-Dybala, M., Uluc, Yis, Caglayan, H., Isapof, A., Marey, I., Panagiotakaki, E., Korff, C., Rossier, E., Riess, A., Beck-Woedl, S., Rauch, A., Zweier, C., Hoyer, J., Reis, A., Mironov, M., Bobylova, M., Mukhin, K., Hernandez-Hernandez, L., Maher, B., Sisodiya, S., Kuhn, M., Glaeser, D., Wechuysen, S., Myers, C. T., Mefford, H. C., Hortnagel, K., Biskup, S., Lemke, J. R., Heron, D., Kluger, G., Depienne, C., Craiu, D., De Jonghe, P., Helbig, I., Guerrini, R., Lehesjoki, A. -E., Marini, C., Muhle, H., Moller, R. S., Neubauer, B., Pal, D., Selmer, K., Stephani, U., Sterbova, K., Striano, P., Talvik, T., von Spiczak, S., Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Université de Lyon, Klinikum Oldenburg [Oldenburg], Zentrum für Kinder- und Jugendmedizin, Dpt of Pediatric Neurology and Developmental Medicine and Epilepsy Center [Munich], University of Munich, Department of Medical Genetics, Institute of Mother and Child, Division of Child Neurology, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Dpt of Molecular Biology and Genetics Istanbul, Boǧaziçi üniversitesi = Boğaziçi University [Istanbul], Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant, Dpt de l'Enfant et de l'Adolescent, Neuropédiatrie [Genève], Hôpitaux Universitaires de Genève (HUG), Institute of Human Genetics [Tuebingen], University of Tuebingen, Institute of Medical Genetics and Applied Genomics [Tübingen], University of Tübingen, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Svt. Luka's Institute of Child Neurology and Epilepsy, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Genetikum, Neurogenetics Group, Division of Genetic Medicine [Seattle], University of Washington [Seattle], CeGaT GmbH, Institut für Humangenetik, Universität Heidelberg [Heidelberg], Mignot, Cyril, von Stülpnagel, Celina, Korff, Christian, EuroEPINOMICS-RES MAE Working Grp, HAL-UPMC, Gestionnaire, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Boğaziçi University [Istanbul], CHU Trousseau [APHP], and Universität Heidelberg [Heidelberg] = Heidelberg University
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, Encephalopathy, Myoclonic Jerk, SYNGAP1, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, fluids and secretions, Medizinische Fakultät, Intellectual disability, mental disorders, Genetics, medicine, ddc:610, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Exome, Genetics (clinical), reproductive and urinary physiology, ddc:618, business.industry, medicine.disease, Hypotonia, 3. Good health, 030104 developmental biology, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Mae Euroepinomics-Res Mae; International audience; Objective We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype–phenotype correlations.Methods We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.Results We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3′ and 5′ exons. Seizures in patients with mutations in exons 4–5 were more pharmacoresponsive than in patients with mutations in exons 8–15.Conclusions SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.
Published: 2016

12. 'Hemispherical asymmetry in the Meyer's Loop': a prospective study of visual-field deficits in 105 cases undergoing anterior temporal lobe resection for epilepsy

Author: Andrew W. McEvoy, Panitha Jindahra, Merle James-Galton, Tak Lap Poon, N. U. Owase Jeelani, Gordon T. Plant, William Harkness, Paul Kabasele, John Stevens, Mandeep S. Tamber, John S. Duncan, Great Ormond Street Hospital for Children [London] (GOSH), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL)-Institute of Neurology, The Hospital for sick children [Toronto] (SickKids), Queen Elizabeth Hospital, Queens Elizabeth Hospital [Birmingham], The National Hospital For Neurology and Neurosurgery, and The National Hospital for Neurology and Neurosurgery
Subjects: Adult, medicine.medical_specialty, genetic structures, Vision Disorders, Functional Laterality, Temporal lobe, Central nervous system disease, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, medicine, Humans, Visual Pathways, Epilepsy surgery, Prospective Studies, Prospective cohort study, EPILEPSY, Amygdalohippocampectomy, Middle Aged, Anterior Temporal Lobectomy, medicine.disease, Magnetic Resonance Imaging, ANATOMY, Surgery, Psychiatry and Mental health, VISION, medicine.anatomical_structure, Epilepsy, Temporal Lobe, Laterality, 030221 ophthalmology & optometry, Neurology (clinical), Visual Fields, Psychology, 030217 neurology & neurosurgery, Optic radiation
Abstract: Objectives Visual-field deficits following temporal lobe surgery have been reported in the literature. In this prospective study, the authors analyse their experience of visual-field deficits in 105 consecutive cases undergoing temporal-lobe surgery performed by a single surgeon, with particular consideration to the laterality of the deficit and its functional implications. Methods 105 consecutive patients undergoing an anterior temporal lobe resection for epilepsy, between March 1998 and June 2004, were selected. The patient population had a mean age of 35 years (range 19–60 years); 53 had a left-sided resection and 52 a right-sided resection. 91 patients had mesial temporal sclerosis, three gangliogliomas, four dysembryoplastic neuroepithelial tumours (DNETs), two neurocytomas and two cavernomas, and in three cases the histology was inconclusive. Pre- and postoperative visual-field tests were obtained using the Humphrey Esterman binocular functional test for all cases. The test was set to stimulus white III, with a single intensity of 10 DB on the background of 31.5 ASB for all patients. A minimum follow-up period of 12 months postsurgery was employed. Postoperative MRI scans were carried out on all patients. 60 scans were randomly selected, and the extent of temporal lobe resection calculated manually for each. Results Of the 105 cases, 16 patients had a visual-field deficit postoperatively which was not present preoperatively: 12 following a left and four following a right-sided resection. The OR for incurring a postoperative visual-field defect following left versus right-sided surgery was 3.51 (95% CI 1.05 to 11.73, p=0.04). In four patients, the deficit was severe enough to preclude them from driving in the UK (three left- and one right-sided resection). There was no association between the extent of tissue resection and the incidence of postoperative visual-field deficits. Conclusions This study suggests left-/right-hemispherical asymmetry in the Geniculocalcarine tracts with field deficits being 3.5 times more likely following left-sided anterior temporal lobe resections compared with right-sided resections. This has significant implications on counselling patients for these procedures. MR tractography may provide an anatomical substrate for these clinical findings, perhaps revealing a more anterior course of the optic radiations within the temporal lobe in one hemisphere versus the other.
Published: 2010

13. Multi-template approaches for segmenting the hippocampus: the case of the SACHA software

Author: Fillon, Ludovic, Colliot, Olivier, Hasboun, Dominique, Dubois, Bruno, Dormont, Didier, Lemieux, Louis, Chupin, Marie, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), CIC AP-HP (pitie-Salpetriere)/inserm, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), MRI Unit, National Society for Epilepsy, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing
Abstract: International audience; The hippocampus has been shown to play a crucial role in memory and learning. Its volumetry is a well-established biomarker of Alzheimer’s Disease (AD) and hippocampal sclerosis in temporal lobe epilepsy (TLE). Manual segmentation being time consuming and suffering from low reproducibility,robust automatic segmentation from routine T1 images is of high interest for studying large datasets. We previously proposed such an approach (SACHA, Chupin et al, 2007, 2009), based on competitive region deformation constrained by both anatomical landmarks and a single probabilistic template of 16 young healthy subjects registered using SPM5. The atlas being introduced as a soft constraint, robust results have been obtained in large series of patients with various pathologies. In recent years, multitemplate approaches have proven to be a powerful mean to increase segmentation robustness (Barnes et al, 2008) (Aljabar et al, 2009) (Heckemann et al 2006), more specifically for subjects with very large atrophy or atypical shapes (such as malrotations (Bernasconi et al, 2005) (Kim et al, 2012)).We propose here to evaluate the introduction of multiple-template constraints in SACHA.
Published: 2015

14. Integrating electrodermal biofeedback into pharmacologic treatment of grand mal seizures

Author: Jean-Arthur Micoulaud-Franchi, Fabrice Bartolomei, Yoko Nagai, Iliana Kotwas, Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Sommeil, Addiction et Neuropsychiatrie [Bordeaux] (SANPSY), Université de Bordeaux (UB)-CHU de Bordeaux Pellegrin [Bordeaux]-Centre National de la Recherche Scientifique (CNRS), Services d’explorations fonctionnelles du système nerveux [CHU Bordeaux] (Clinique du Sommeil), CHU Bordeaux [Bordeaux], Service de neurophysiologie clinique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Epilepsies, Lesions Cerebrales et Systemes Neuraux de la Cognition, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Psychiatry Department [London, UK] (Brighton and Sussex Medical School), University of Sussex, Department of Clinical and Experimental Epilepsy [London, UK] (Institute of Neurology), University College of London [London] (UCL), Sommeil, Attention et Neuropsychiatrie [Bordeaux] (SANPSY), University of Sussex [London, UK], and Kotwas, Iliana
Subjects: biofeedback, medicine.medical_specialty, medicine.medical_treatment, Psychological intervention, Single-subject design, Biofeedback, Pharmacological treatment, Arousal, lcsh:RC321-571, Behavioral Neuroscience, Epilepsy, Physical medicine and rehabilitation, Medicine, Psychiatry, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, ComputingMilieux_MISCELLANEOUS, Relaxation (psychology), General Commentary, business.industry, medicine.disease, electrodermal activity, 3. Good health, Psychiatry and Mental health, Neuropsychology and Physiological Psychology, Anticonvulsant, Neurology, [SCCO.PSYC] Cognitive science/Psychology, [SCCO.PSYC]Cognitive science/Psychology, epilepsy, sympathetic arousal, business, self-efficacy, Neuroscience
Abstract: Thirty percent of patients with epilepsy experience seizures despite optimal anticonvulsant drug treatment. Stress is frequently identified by patients with epilepsy as a precipitant of seizures (Spector et al., 2000; Ferlisi and Shorvon, 2014). Patients also often report using countermeasures to control the seizure onset. These are typically spontaneous and individualized such as increasing arousal by walking, breathing, standing, focusing attention, changing way of thinking, and more rarely inducing relaxation (Lee and No, 2005; Hether et al., 2013). In parallel, behavioral and psychological interventions, complementing conventional therapeutic methods for the management of epileptic seizures, have gained greater clinical attention over the past decade. Among these, Biofeedback (BFK) represents a noninvasive biobehavioral treatment that enables a patient to gain volitional control over a specific physiological process. BFK has already shown its value when applied to patients with epilepsy (Sterman and Friar, 1972; Rockstroh et al., 1993; Nagai et al., 2004a; Nagai, 2011; Micoulaud-Franchi et al., 2014a,b). Scrimali et al. (2015) have rightly pointed out the potential usefulness of electrodermal biofeedback in the management of refractory epilepsy. In a single case study, they report an effect of electrodermal activity (EDA) relaxation biofeedback in reducing seizures in a patient treated for 2 years. This case study supports the necessity to expand clinical armamentarium for treatment-resistant patients with few alternatives.
Published: 2015

15. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author: Salpietro, Vincenzo, Dixon, Christine L, Guo, Hui, Bello, Oscar D, Vandrovcova, Jana, Efthymiou, Stephanie, Raspall Chaure, Miquel, Macaya Ruíz, Alfons, Institut Català de la Salut, [Salpietro V] Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto 'Giannina Gaslini', Genoa, Italy. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy. [Dixon CL, Bello OD] Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. [Guo H] Department of Genome Sciences, University of Washington School of Medicine, Seattle, USA. Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China. [Vandrovcova J] Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK. [Efthymiou S] Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. [Raspall-Chaure M, Macaya A] Servei de Neurologia Pediatrica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain., Hospital Universitari Vall d'Hebron, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Trastornos Mentales::Trastornos del Neurodesarrollo [PSIQUIATRÍA Y PSICOLOGÍA], Otros calificadores::Otros calificadores::/genética [Otros calificadores], trastornos mentales::trastornos del desarrollo neurológico [PSIQUIATRÍA Y PSICOLOGÍA], Mutació (Biologia), Proteïnes de membrana, Other subheadings::Other subheadings::/genetics [Other subheadings], Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::Ion Channels::Ligand-Gated Ion Channels::Receptors, Ionotropic Glutamate::Receptors, AMPA [CHEMICALS AND DRUGS], Trastorns del desenvolupament - Aspectes genètics, Aminoácidos, Péptidos y Proteínas::Proteínas::Proteínas Portadoras::Proteínas de Transporte de Membrana::Canales Iónicos::Canales Iónicos Activados por Ligandos::Receptores Ionotrópicos de Glutamato::Receptores AMPA [COMPUESTOS QUÍMICOS Y DROGAS], fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], aminoácidos, péptidos y proteínas::proteínas::proteínas transportadoras::proteínas de transporte de membrana::canales iónicos::canales iónicos de apertura por ligandos::receptores ionotrópicos de glutamato::receptores AMPA [COMPUESTOS QUÍMICOS Y DROGAS], Mental Disorders::Neurodevelopmental Disorders [PSYCHIATRY AND PSYCHOLOGY]
Abstract: Neurodevelopmental disorders; AMPA; GluA2 Trastorns del neurodesenvolupament; AMPA; GluA2 Trastornos del neurodesarrollo; AMPA; GluA2 AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. Supported by the Wellcome Trust (WT093205MA and WT104033AIA), Medical Research Council (H.H. and D.M.K.), European Community’s Seventh Framework Programme (FP7/2007‐2013, under grant agreement No. 2012‐305121 to H.H.), Muscular Dystrophy Association (MDA), Muscular Dystrophy UK, The MSA Trust, Ataxia UK, The Sparkes Children’s Medical Research Charity, The Great Ormond Street Hospital Charity, Rosetrees Trust, Brain Research UK, The UK HSP Society, The European Union’s Horizon 2020 research and innovation programme Solve-RD project (No 779257), The Pakistan Council (Scholarship to HT), The National Natural Science Foundation of China (31671114, 81871079, 81330027, and 81525007 to H.G. and K.X.), the US National Institutes of Health (NIH grant R01MH101221 to E.E.E), the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) and the Biomedical Research Centre (BRC)

16. Attenuation correction synthesis for hybrid PET-MR scanners: Application to brain studies

Author: Burgos, Ninon, Cardoso, M. J., Thielemans, K., Modat, M., Pedemonte, S., Dickson, J., Barnes, A., Ahmed, R., Mahoney, C. J., Schott, J. M., Duncan, J. S., Atkinson, D., Arridge, S. R., Hutton, B. F., Ourselin, S., Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Clinical Sciences Centre, Medical Research Council, Epilepsy Society, Department of Clinical and Experimental Epilepsy, and UCL Institute of Neurology
Subjects: computerised tomography, local image similarity measure, positron emission tomography, Attenuation correction, data acquisition, segmentation method, brain, visual databases, biomedical MRI, image matching, patient-specific attenuation map, medical image processing, biomedical equipment, CT synthesis, Databases, computed tomography image, simplified atlas-based method, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, magnetic resonance imaging, synthetic attenuation map generation, database of MRI-CT pair matching, PET-CT acquisition system, Computed tomography, Accuracy, multi-atlas information propagation scheme, PET reconstruction accuracy, Bones, synthetic CT image generation, Attenuation, attenuation correction synthesis, brain study application, Image synthesis, image reconstruction, MRI-derived patient morphology matching, positron emission tomography data quantification, attenuation correction improvement, MRI image, hybrid PET-MR scanner, ultrashort-echo-time MRI sequence, positron emission tomography/magnetic resonance (PET/MR), neurophysiology
Abstract: 00104; International audience; Attenuation correction is an essential requirement for quantification of positron emission tomography (PET) data. In PET/CT acquisition systems, attenuation maps are derived from computed tomography (CT) images. However, in hybrid PET/MR scanners, magnetic resonance imaging (MRI) images do not directly provide a patient-specific attenuation map. The aim of the proposed work is to improve attenuation correction for PET/MR scanners by generating synthetic CTs and attenuation maps. The synthetic images are generated through a multi-atlas information propagation scheme, locally matching the MRI-derived patient's morphology to a database of MRI/CT pairs, using a local image similarity measure. Results show significant improvements in CT synthesis and PET reconstruction accuracy when compared to a segmentation method using an ultrashort-echo-time MRI sequence and to a simplified atlas-based method.
Published: 2014

17. Effect of scatter correction when comparing attenuation maps: Application to brain PET/MR

Author: John Dickson, Brian Hutton, Sebastien Ourselin, Ninon Burgos, Pawel J. Markiewicz, David Atkinson, John S. Duncan, Kris Thielemans, Simon R. Arridge, Jieqing Jiao, M. Jorge Cardoso, Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Clinical Sciences Centre, Medical Research Council, Epilepsy Society, Department of Clinical and Experimental Epilepsy, and UCL Institute of Neurology
Subjects: Physics, medicine.medical_specialty, positron emission tomography, medicine.diagnostic_test, attenuation correction methods, scatter estimation strategies, brain, Attenuation, Context (language use), Pet imaging, Image segmentation, Iterative reconstruction, Radionuclide uptake, medical image processing, Positron emission tomography, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, magnetic resonance imaging, Radiology, Scatter correction, Biomedical engineering
Abstract: International audience; In PET imaging, attenuation and scatter corrections are an essential requirement to accurately quantify the radionuclide uptake. In the context of PET/MR scanners, obtaining the attenuation information can be challenging. Various authors have quantified the effect of an imprecise attenuation map on the reconstructed PET image but its influence on scatter correction has usually been ignored. In this paper, we investigate the effects of imperfect attenuation maps (μmaps) on the scatter correction in a simulation setting. We focused our study on three μmaps: the reference μmap derived from a CT image, and two MR-based methods. Two scatter estimation strategies were implemented: a μmap-specific scatter estimation and an ideal scatter estimation relying only on the reference CT μmap. The scatter estimation used the Single Scatter Simulation algorithm with tail-fitting. The results show that, for FDG brain PET, regardless of the μmap used in the reconstruction, the difference on PET images between μmap-specific and ideal scatter estimations is small (less than 1%). More importantly, the relative error between attenuation correction methods does not change depending on the scatter estimation method included in the simulation and reconstruction process. This means that the effect of errors in the μmap on the PET image is dominated by the attenuation correction, while the scatter estimate is relatively unaffected. Therefore, while scatter correction improves reconstruction accuracy, it is unnecessary to include scatter in the simulation when comparing different attenuation correction methods for brain PET/MR.
Published: 2014

18. Attenuation correction synthesis for hybrid PET-MR scanners: validation for brain study applications

Author: Sebastien Ourselin, David Atkinson, Brian F. Hutton, Ninon Burgos, Simon R. Arridge, M. Jorge Cardoso, John S. Duncan, Kris Thielemans, Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Epilepsy Society, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, and Centre for Medical Imaging, University College London, London, United Kingdom
Subjects: Ground truth, Radiation, business.industry, Computer science, Attenuation, Biomedical Engineering, Image registration, Pattern recognition, Gold standard (test), Similarity measure, Weighting, Transformation (function), Meeting Abstract, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Radiology, Nuclear Medicine and imaging, Artificial intelligence, Nuclear medicine, business, Instrumentation, Correction for attenuation, ComputingMilieux_MISCELLANEOUS
Abstract: In this work, we further validate a CT and attenuation map (μ-map) synthesis algorithm [1]. The CT synthesis method relies on a pre-acquired set of aligned MRI/CT pairs from multiple subjects. Each MRI from the database is non-rigidly registered to the target MRI. The CTs in the database are then mapped using the same transformation to the target MRI. A local image similarity measure between the target MRI and the set of registered MRIs is used as a surrogate of the underlying morphological similarity. Finally, the synthetic CT is generated using a voxel-wise weighting scheme, and converted to linear attenuation coefficients by a piecewise linear transformation. Following the proposed method, a pseudo CT (pCT) was generated using only the MRI of the subject and compared to the ground truth CT, validating the accuracy of the CT synthesis. A PET image (PETpCT) was then reconstructed with an off-line version of the Siemens Healthcare reconstruction software using the pCT μ-map, and compared with the gold standard PET reconstructed using the CT μ-map. We validated our method for brain-related applications with 16 subjects and compared our solution to: a simpler atlas-based method, named the best-atlas method
Published: 2014

19. Attenuation correction synthesis for hybrid PET-MR scanners

Author: Anna Barnes, Brian F. Hutton, John S. Duncan, John Dickson, Manuel Jorge Cardoso, Stefano Pedemonte, Marc Modat, Sebastien Ourselin, David Atkinson, Simon R. Arridge, Ninon Burgos, Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Epilepsy Society, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, and Centre for Medical Imaging, University College London, London, United Kingdom
Subjects: Computer science, Computed tomography, Multimodal Imaging, Sensitivity and Specificity, 030218 nuclear medicine & medical imaging, Pattern Recognition, Automated, 03 medical and health sciences, 0302 clinical medicine, Image Interpretation, Computer-Assisted, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, Humans, Segmentation, Multimodal imaging, medicine.diagnostic_test, business.industry, Attenuation, Radiation dose, Reproducibility of Results, Magnetic resonance imaging, Image Enhancement, Magnetic Resonance Imaging, Positron emission tomography, 030220 oncology & carcinogenesis, Positron-Emission Tomography, Nuclear medicine, business, Artifacts, Correction for attenuation, Preclinical imaging, Algorithms
Abstract: International audience; The combination of functional and anatomical imaging technologies such as Positron Emission Tomography (PET) and Computed Tomography (CT) has shown its value in the preclinical and clinical fields. In PET/CT hybrid acquisition systems, CT-derived attenuation maps enable a more accurate PET reconstruction. However, CT provides only very limited soft-tissue contrast and exposes the patient to an additional radiation dose. In comparison, Magnetic Resonance Imaging (MRI) provides good soft-tissue contrast and the ability to study functional activation and tissue microstructures, but does not directly provide patient-specific electron density maps for PET reconstruction.The aim of the proposed work is to improve PET/MR reconstruction by generating synthetic CTs and attenuation-maps. The synthetic images are generated through a multi-atlas information propagation scheme, locally matching the MRI-derived patient’s morphology to a database of pre-acquired MRI/CT pairs. Results show improvements in CT synthesis and PET reconstruction accuracy when compared to a segmentation method using an Ultrashort-Echo-Time MRI sequence.
Published: 2014

20. Simulated Field Maps: Toward Improved Susceptibility Artefact Correction in Interventional MRI

Author: Ninon Burgos, M. Jorge Cardoso, Mark White, Sebastien Ourselin, Pankaj Daga, John S. Thornton, Laura Mancini, Tarek A. Yousry, Danail Stoyanov, Gavin P. Winston, Andrew W. McEvoy, Martin Kochan, John S. Duncan, Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Lysholm Department of Neuroradiology, National Hospital for Neurology & Neurosurgery, University College London Hospitals (UCLH), Epilepsy Society, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Laser Radars Laboratory [Sofia], and Bulgarian Academy of Sciences (BAS)
Subjects: Modality (human–computer interaction), business.industry, Interventional magnetic resonance imaging, Lobe, Field (computer science), 030218 nuclear medicine & medical imaging, Resection, Temporal lobe, Intraoperative MRI, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Medicine, Segmentation, Computer vision, Artificial intelligence, business, 030217 neurology & neurosurgery
Abstract: International audience; Intraoperative MRI is a powerful modality for acquiring structural and functional images of the brain to enable precise image-guided neurosurgery. In this paper, we propose a novel method for simulating main magnetic field inhomogeneity maps during intraoperative MRI-guided neurosurgery. Our method relies on an air-tissue segmentation of intraoperative patient specific data, which is used as an input to a subsequent field simulation step. The generated simulation can then be used to enhance the precision of image-guidance. We report results of our method on 12 patient datasets acquired during image-guided neurosurgery for anterior lobe resection for surgical management of focal temporal lobe epilepsy. We find a close agreement between the field inhomogeneity maps acquired as part of the imaging protocol and the simulated field inhomogeneity maps generated by the proposed method.
Published: 2014

21. Interictal functional connectivity of human epileptic networks assessed by intracerebral EEG and BOLD signal fluctuations

Author: Patrick J. Cozzone, Fabrice Wendling, Christian Bénar, Gaelle Bettus, Patrick Chauvel, Louis Lemieux, Fabrice Bartolomei, Jean Régis, Jean-Philippe Ranjeva, Maxime Guye, Sylviane Confort-Gouny, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Epilepsies, Lesions Cerebrales et Systemes Neuraux de la Cognition, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle de Neurosciences Cliniques, Assistance Publique - Hôpitaux de Marseille (APHM), Pôle d'imagerie Médicale, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), MRI Unit, National Society for Epilepsy, This work was supported by CNRS, INSERM, Agence Nationale de la Recherche (ANR, CONNECTEPI) and ADEREM., Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Le Corre, Morgane
Subjects: Anatomy and Physiology, genetic structures, lcsh:Medicine, Neuroimaging, Biology, Electroencephalography, Temporal lobe, MESH: Magnetic Resonance Imaging, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Temporal Lobe Epilepsy, MESH: Electroencephalography, medicine, Humans, Premovement neuronal activity, Ictal, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:Science, 030304 developmental biology, [SDV.IB] Life Sciences [q-bio]/Bioengineering, 0303 health sciences, Multidisciplinary, Blood-oxygen-level dependent, MESH: Humans, medicine.diagnostic_test, Resting state fMRI, fMRI, lcsh:R, Connectomics, medicine.disease, Magnetic Resonance Imaging, Electrophysiology, Neuroanatomy, Neurology, nervous system, MESH: Epilepsy, Medicine, lcsh:Q, [SDV.IB]Life Sciences [q-bio]/Bioengineering, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Functional magnetic resonance imaging, Neuroscience, 030217 neurology & neurosurgery, Research Article
Abstract: International audience; In this study, we aimed to demonstrate whether spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal derived from resting state functional magnetic resonance imaging (fMRI) reflect spontaneous neuronal activity in pathological brain regions as well as in regions spared by epileptiform discharges. This is a crucial issue as coherent fluctuations of fMRI signals between remote brain areas are now widely used to define functional connectivity in physiology and in pathophysiology. We quantified functional connectivity using non-linear measures of cross-correlation between signals obtained from intracerebral EEG (iEEG) and resting-state functional MRI (fMRI) in 5 patients suffering from intractable temporal lobe epilepsy (TLE). Functional connectivity was quantified with both modalities in areas exhibiting different electrophysiological states (epileptic and non affected regions) during the interictal period. Functional connectivity as measured from the iEEG signal was higher in regions affected by electrical epileptiform abnormalities relative to non-affected areas, whereas an opposite pattern was found for functional connectivity measured from the BOLD signal. Significant negative correlations were found between the functional connectivities of iEEG and BOLD signal when considering all pairs of signals (theta, alpha, beta and broadband) and when considering pairs of signals in regions spared by epileptiform discharges (in broadband signal). This suggests differential effects of epileptic phenomena on electrophysiological and hemodynamic signals and/or an alteration of the neurovascular coupling secondary to pathological plasticity in TLE even in regions spared by epileptiform discharges. In addition, indices of directionality calculated from both modalities were consistent showing that the epileptogenic regions exert a significant influence onto the non epileptic areas during the interictal period. This study shows that functional connectivity measured by iEEG and BOLD signals give complementary but sometimes inconsistent information in TLE.
Published: 2011

22. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission

Author: Blümcke, Ingmar, Thom, Maria, Aronica, Eleonora, Armstrong, Dawna, Vinters, Harry, Palmini, Andre, Jacques, Thomas, Avanzini, Giuliano, Barkovich, James, Battaglia, Giorgio, Becker, Albert, Cepeda, Carlos, Cendes, Fernando, Colombo, Nadia, Peter, Crino, Cross, Helen, Delalande, Olivier, Dubeau, François, Duncan, John, Guerrini, Renzo, Kahane, Philippe, Mathern, Gary, Najm, Imad, Ozkara, Ciğdem, Raybaud, Charles, Represa, Alfonso, Roper, Steven, Salamon, Noriko, Schulze-Bonhage, Andreas, Tassi, Laura, Vezzani, Annamaria, Spreafico, Roberto, Department of Neuropathology, University Hospital Erlangen = Uniklinikum Erlangen, University College of London [London] (UCL)-Institute of Neurology, Department of (Neuro)Pathology, Academic Medisch Centrum, University of Amsterdam [Amsterdam] (UvA)-Stichting Epilepsie Instellingen Nederland (SEIN), Texas Children's Hospital [Houston, USA], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Servico de Neurologia, Universidade Catolica do Rio Grande do Sul-Hospital Sao Lucas da Pontifica, UCL-Institute of Child Health (ICH), Great Ormond Street Hospital for Children [London] (GOSH)-Institute of Child Health, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Department of Neuroradiology, University of California [San Francisco] (UC San Francisco), Molecular Neuroanatomy and Pathogenesis Unit, University of Bonn Medical Center, Intellectual and Developmental Disabilities Research Center (IDDRC), UCLA Medical Center-Semel Institute, Department of Neurology, Universidade Estadual de Campinas = University of Campinas (UNICAMP), Ospedale Niguardia, PENN Epilepsy Center, University of Pennsylvania, The Prince of Wales's Chair of Childhood Epilepsy, Great Ormond Street Hospital for Children [London] (GOSH)-UCL-Institute of Child Health-National Centre for Young People with Epilepsy, Service de Neurochirurgie Pediatrique, Fondation Ophtalmologique Rotschild, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Department of Clinical and Experimental Epilepsy, Pediatric Neurology Unit and Laboratories, Università degli Studi di Firenze = University of Florence (UniFI)-Children's Hospital A. Meyer, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de neurologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Departments of Neurosurgery, Psychiatry and Behavioral Science, David Geffen School of Medicine [Los Angeles], Neurological Institute, Cleveland Clinic, Cerrahpasa Medical Faculty-Istanbul University, Division of Neuroradiology, Hospital for Sick Children-Department of Diagnostic Imaging, Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neurosurgery, University of Florida [Gainesville] (UF), Departement of Radiology, Epilepsy Centre, University Hospital Freiburg, Centre « Claudio-Munari » pour la chirurgie de l'épilepsie et du Parkinson, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Neuroscience, Mario Negri Institute for Pharmacological Research - Milan, Janssen- Cilag, UCB, GSK, NIH R01 NS38992, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Neurology, Pathology, University Hospital Erlangen, University of Amsterdam [Amsterdam] (UvA)-Stichting Epilepsie Instellingen Nederland, University of California-University of California-University of California [Los Angeles] (UCLA), University of California-University of California, University of California [San Francisco] (UCSF), University of Campinas [Campinas] (UNICAMP), University of Pennsylvania [Philadelphia], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-Children's Hospital A. Meyer, Istanbul University -Cerrahpasa Medical Faculty, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Deransart, Colin
Subjects: Cerebral Cortex, clinicopathologic spectrum, MESH: Humans, Advisory Committees, MESH: Societies, Medical, Global Health, Article, MESH: Cerebral Cortex, Malformations of Cortical Development, MESH: Malformations of Cortical Development, epilepsy, Humans, MESH: Advisory Committees, cortical dysplasia, Societies, Medical, MESH: World Health
Abstract: Focal cortical dysplasias (FCDs) are localized regions of malformed cerebral cortex and are very frequently associated with epilepsy in both children and adults. A broad spectrum of histopathology has been included in the diagnosis of FCD. Characteristic findings include aberrant radial or tangential lamination of the neocortex (FCD Type I) and cytological abnormalities (FCD Type II). An ILAE task force has re-evaluated available data and proposes a clinico-pathologic classification system of FCDs. The major change since a prior classification represents the introduction of FCD Type III, which occurs in combination with Hippocampal Sclerosis (FCD Type IIIa), or with epilepsy-associated tumors (FCD Type IIIb). FCD Type IIIc is found adjacent to vascular malformations, whereas FCD Type IIId can be diagnosed in association with epileptogenic lesions acquired in early life (i.e., traumatic injury, ischemic injury or encephalitis). Hence, FCD Type I will now refer to isolated lesions, which present either as radial (FCD Type Ia) or tangential (FCD Type Ib) dyslamination of the neocortex, microscopically identified in one or multiple lobes. FCD Type II is an isolated lesion characterized by cortical dyslamination and dysmorphic neurons without (Type IIa) or with balloon cells (Type IIb). Architectural abnormalities adjacent to or within gross malformations of cortical development are frequently observed and not distinguished as a specific FCD variant. This three-tiered classification system will help to better characterize specific clinico-pathological entities and is an important basis to further explore imaging, electro-clinical features, and postsurgical seizure control as well as underlying molecular pathomechanisms.
Published: 2011

23. Automatic segmentation of the hippocampus and the amygdala driven by hybrid constraints: Method and validation

Author: Eric Bardinet, Jane L. Burdett, John S. Duncan, Marie Chupin, Louis Lemieux, Alexander Hammers, Rebecca S. N. Liu, Line Garnero, Olivier Colliot, Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MRC Clinical Sciences Centre and Division of Medicine, Imperial College London, The Neurodis Fondation, Neurodis, Neurosciences cognitives et imagerie cérébrale (NCIC), Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Neuro-Imagerie de Recherche (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, Male, Computer science, Cognitive Neuroscience, Hippocampus, Sensitivity and Specificity, 030218 nuclear medicine & medical imaging, Pattern Recognition, Automated, 03 medical and health sciences, 0302 clinical medicine, Imaging, Three-Dimensional, Atlas (anatomy), Artificial Intelligence, Image Interpretation, Computer-Assisted, medicine, Technical Note, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Brain segmentation, Hippocampus (mythology), Humans, Segmentation, Computer vision, Hippocampal sclerosis, medicine.diagnostic_test, business.industry, Reproducibility of Results, Pattern recognition, Magnetic resonance imaging, Image segmentation, medicine.disease, Amygdala, Image Enhancement, Magnetic Resonance Imaging, medicine.anatomical_structure, Neurology, Cohort, Female, Artificial intelligence, business, 030217 neurology & neurosurgery, Algorithms
Abstract: International audience; The segmentation from MRI of macroscopically ill-defined and highly variable structures, such as the hippocampus (Hc) and the amygdala (Am), requires the use of specific constraints. Here, we describe and evaluate a fast fully automatic hybrid segmentation that uses knowledge derived from probabilistic atlases and anatomical landmarks, adapted from a semi-automatic method. The algorithm was designed at the outset for application on images from healthy subjects and patients with hippocampal sclerosis. Probabilistic atlases were built from 16 healthy subjects, registered using SPM5. Local mismatch in the atlas registration step was automatically detected and corrected. Quantitative evaluation with respect to manual segmentations was performed on the 16 young subjects, with a leave-one-out strategy, a mixed cohort of 8 controls and 15 patients with epilepsy with variable degrees of hippocampal sclerosis, and 8 healthy subjects acquired on a 3 T scanner. Seven performance indices were computed, among which error on volumes RV and Dice overlap K. The method proved to be fast, robust and accurate. For Hc, results with the new method were: 16 young subjects {RV=5%, K=87%}; mixed cohort {RV=8%, K=84%}; 3 T cohort {RV=9%, K=85%}. Results were better than with atlas-based (thresholded probability map) or semi-automatic segmentations. Atlas mismatch detection and correction proved efficient for the most sclerotic Hc. For Am, results were: 16 young controls {RV=7%, K=85%}; mixed cohort {RV=19%, K=78%}; 3 T cohort {RV=10%, K=77%}. Results were better than with the semi-automatic segmentation, and were also better than atlas-based segmentations for the 16 young subjects.
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24. Organoids as a model of status epilepticus.

Author: Street JS, Zourray C, and Lignani G
Abstract: Status epilepticus (SE) is a neurological emergency that can be studied in animal models, particularly mice. However, these models are labour-intensive and require large numbers of animals, which raises ethical and logistical challenges. Additionally, rodent-based models could lack direct relevance to human physiology. While reduced models offer some insights, they fail to replicate the full complexity of brain connectivity and interactions with other organs. To address this, human forebrain assembloids, formed by both cortical excitatory and subpallial inhibitory neurons, could be an alternative SE model. Assembloids offer a middle ground, enabling high-throughput screening of potential treatments while maintaining relevant human cell biology. This approach could serve as an intermediate step before transitioning to animal models, ultimately reducing the time and number of animals required for SE research. This paper is based on a presentation made at the 9thLondon-Innsbruck Colloquium on Status Epilepticus and Acute Seizures in April 2024., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Gabriele Lignani reports financial support was provided by Great Ormond Street Hospital for Children NHS Foundation Trust. Gabriele Lignani reports financial support was provided by UK Research and Innovation. Gabriele Lignani reports financial support was provided by UK Research and Innovation Medical Research Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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25. A Quantitative Comparison Between Human and Artificial Intelligence in the Detection of Focal Cortical Dysplasia.

Author: Walger L, Bauer T, Kügler D, Schmitz MH, Schuch F, Arendt C, Baumgartner T, Birkenheier J, Borger V, Endler C, Grau F, Immanuel C, Kölle M, Kupczyk P, Lakghomi A, Mackert S, Neuhaus E, Nordsiek J, Odenthal AM, Dague KO, Ostermann L, Pukropski J, Racz A, von der Ropp K, Schmeel FC, Schrader F, Sitter A, Unruh-Pinheiro A, Voigt M, Vychopen M, von Wedel P, von Wrede R, Attenberger U, Vatter H, Philipsen A, Becker A, Reuter M, Hattingen E, Sander JW, Radbruch A, Surges R, and Rüber T
Abstract: Objectives: Artificial intelligence (AI) is thought to improve lesion detection. However, a lack of knowledge about human performance prevents a comparative evaluation of AI and an accurate assessment of its impact on clinical decision-making. The objective of this work is to quantitatively evaluate the ability of humans to detect focal cortical dysplasia (FCD), compare it to state-of-the-art AI, and determine how it may aid diagnostics., Materials and Methods: We prospectively recorded the performance of readers in detecting FCDs using single points and 3-dimensional bounding boxes. We acquired predictions of 3 AI models for the same dataset and compared these to readers. Finally, we analyzed pairwise combinations of readers and models., Results: Twenty-eight readers, including 20 nonexpert and 5 expert physicians, reviewed 180 cases: 146 subjects with FCD (median age: 25, interquartile range: 18) and 34 healthy control subjects (median age: 43, interquartile range: 19). Nonexpert readers detected 47% (95% confidence interval [CI]: 46, 49) of FCDs, whereas experts detected 68% (95% CI: 65, 71). The 3 AI models detected 32%, 51%, and 72% of FCDs, respectively. The latter, however, also predicted more than 13 false-positive clusters per subject on average. Human performance was improved in the presence of a transmantle sign ( P < 0.001) and cortical thickening ( P < 0.001). In contrast, AI models were sensitive to abnormal gyration ( P < 0.01) or gray-white matter blurring ( P < 0.01). Compared with single experts, expert-expert pairs detected 13% (95% CI: 9, 18) more FCDs ( P < 0.001). All AI models increased expert detection rates by up to 19% (95% CI: 15, 24) ( P < 0.001). Nonexpert+AI pairs could still outperform single experts by up to 13% (95% CI: 10, 17)., Conclusions: This study pioneers the comparative evaluation of humans and AI for FCD lesion detection. It shows that AI and human predictions differ, especially for certain MRI features of FCD, and, thus, how AI may complement the diagnostic workup., Competing Interests: Conflicts of interest and sources of funding: A.R. has received fees as a speaker from UCB Pharma and travel support from the Elisabeth und Helmut Uhl Stiftung. U.A. has received fees as a speaker for Siemens Healthineers and as clinical consultant for Bayer. A.R. lectures for Guerbet and Bayer, and is part of the Advisory Board for GE, Bracco, and Guerbet. R.S. has received personal fees as speaker or for serving on advisory boards from Angelini, Arvelle, Bial, Desitin, Eisai, Jazz Pharmaceuticals Germany GmbH, Janssen-Cilag GmbH, LivaNova, LivAssured B.V., Novartis, Precisis GmbH, Rapport Therapeutics, Tabuk Pharmaceuticals, UCB Pharma, UNEEG, and Zogenix. T.R. has received fees as a speaker from Eisai. None of the previously mentioned activities were related to the content of this manuscript. The remaining authors have nothing to declare. No external funding was received for this work., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
Published: 2024
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26. Deciphering temporal gene expression dynamics during epilepsy development using a rat model of focal neocortical epilepsy.

Author: Chang BL, Walker MC, Kullmann DM, and Schorge S
Abstract: Objective: Epilepsy involves significant changes in neural cells during epileptogenesis. Although the molecular mechanism of epileptogenesis remains obscure, changes in gene regulation play a crucial role in the evolution of epilepsy. This study aimed to compare changes in a subset of specific genes during epilepsy development, focusing on the period after the first spontaneous seizure, to identify critical time windows for targeting different regulators., Methods: Using a rat model of acquired focal neocortical epilepsy induced by tetanus toxin, we characterized gene expression at acute, subacute, and chronic stages (48-72 h, 2 weeks, and 30 days after first spontaneous seizure, respectively), focusing on genes' potential contribution to epilepsy progression., Results: We observed dynamic changes in the expression of these genes throughout the period after the first spontaneous seizure. Astrocytic reactions primarily occur early, before epilepsy is well established. Changes in Mtor (mammalian target of rapamycin) and Rest (repressor element 1 silencing transcription factor) signaling pathways are highly dynamic and correlated with the progression of epilepsy development. Ccl2 (chemokine C-C-motif ligand) is upregulated at the chronic stage, indicating activation of the neuroinflammatory pathway. Finally, Gabra5 (γ-aminobutyric acidergic signaling) is downregulated at the late stage after epilepsy is established. Surprisingly, changes in the expression of specific genes are linked to the time since the first seizure, rather than seizure frequency or duration., Significance: These results suggest that the regulation of specific genes is essentially stage-dependent during the development of epilepsy, highlighting the importance of targeting specific genes at appropriate stages of epilepsy development., (© 2024 International League Against Epilepsy.)
Published: 2024
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27. The prevalence of chronic traumatic encephalopathy in a historical epilepsy post-mortem collection.

Author: Ryniejska M, El-Hachami H, Mrzyglod A, Liu J, and Thom M
Abstract: Previous post-mortem epilepsy series showed phosphorylated tau (pTau) accumulation in relation to traumatic brain injury (TBI) rather than driven by seizure frequency. The Corsellis Epilepsy Collection, established in the mid-20th century, represents brain samples collected from patients living with a range of epilepsies from the 1880s to 1990s. Our aim was to interrogate this historical archive to explore relationships between epilepsy, trauma and tau pathology. AT8 immunohistochemistry for pTau was carried out in 102 cases (55% male, with mean age at death of 62 years) on frontal, temporal, amygdala, hippocampal and lesional cortical regions and evaluated using current NINDS criteria for chronic traumatic encephalopathy (CTE) and Braak staging with beta-amyloid, AT8-GFAP and other pTau markers (CP13, PHF1, AT100, AT180) in selected cases. CTE-neuropathologic change (CTE-NC) was identified in 15.7% and was associated with the presence of astroglial tau, a younger age of onset of epilepsy, evidence of TBI and institutionalisation for epilepsy compared to cases without CTE-NC, but not for seizure type or frequency. Memory impairment was noted in 43% of cases with CTE-NC, and a significantly younger age of death; more frequent reports of sudden and unexpected death (p <0.05-0.001) were noted in cases with CTE-NC. In contrast, a higher Braak stage was associated with late-onset epilepsy and cognitive decline. Of note, 9% of cases showed no pTau, including cases with long epilepsy duration, poor seizure control and a history of prior TBI. In summary, this cohort includes patients with more severe and diverse forms of epilepsy, with CTE-NC observed more frequently than reported in non-epilepsy community-based studies (0%-8%) but lower than published series from contact sports participants (32%-87%). Although the literature does not report increased epilepsy occurring in CTE syndrome, our findings support an increased risk of CTE in epilepsy syndromes, likely primarily related to increased TBI., (© 2024 The Author(s). Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)
Published: 2024
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28. Long-term neuroplasticity in language networks after anterior temporal lobe resection.

Author: Sablik M, Fleury MN, Binding LP, Carey DP, d'Avossa G, Baxendale S, Winston GP, Duncan JS, and Sidhu MK
Abstract: Objective: Anterior temporal lobe resection (ATLR) is an effective treatment for drug-resistant temporal lobe epilepsy (TLE), although language deficits may occur after both left and right ATLR. Functional reorganization of the language network has been observed in the ipsilateral and contralateral hemispheres within 12 months after ATLR, but little is known of longer-term plasticity effects. Our aim was to examine the plasticity of language functions up to a decade after ATLR, in relation to cognitive profiles., Methods: We examined 24 TLE patients (12 left [LTLE]) and 10 controls across four time points: pre-surgery, 4 months, 12 months, and ~9 years post-ATLR. Participants underwent standard neuropsychological assessments (naming, phonemic, and categorical fluency tests) and a verbal fluency functional magnetic resonance imaging (fMRI) task. Using a flexible factorial design, we analyzed longitudinal fMRI activations from 12 months to ~9 years post-ATLR, relative to controls, with separate analyses for people with hippocampal sclerosis (HS). Change in cognitive profiles was correlated with the long-term change in fMRI activations to determine the "efficiency" of reorganized networks., Results: LTLE patients had increased long-term engagement of the left extra-temporal and contralateral temporal regions, with better language performance linked to bilateral activation. Those with HS exhibited more widespread bilateral activations. RTLE patients showed plasticity in the left extra-temporal regions, with better language outcomes associated with these areas. Both groups of patients achieved cognitive stability over 9 years, with more than 50% of LTLE patients improving. Older age, longer epilepsy duration, and lower pre-operative cognitive reserve negatively affected long-term language performance., Significance: Neuroplasticity continues for up to ~9 years post-epilepsy surgery in LTLE and RTLE, with effective language recovery linked to bilateral engagement of temporal and extra-temporal regions. This adaptive reorganization is associated with improved cognitive outcomes, challenging the traditional view of localized surgery effects. These findings emphasize the need for early intervention, tailored pre-operative counseling, and the potential for continued cognitive gains with extended post-ATLR rehabilitation., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Published: 2024
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29. Imaging blood-brain barrier dysfunction in drug-resistant epilepsy: A multi-center feasibility study.

Author: Cafri N, Mirloo S, Zarhin D, Kamintsky L, Serlin Y, Alhadeed L, Goldberg I, Maclean MA, Whatley B, Urman I, Doherty CP, Greene C, Behan C, Brennan D, Campbell M, Bowen C, Ben-Arie G, Shelef I, Wandschneider B, Koepp M, Friedman A, and Benninger F
Abstract: Objective: Blood-brain barrier dysfunction (BBBD) has been linked to various neurological disorders, including epilepsy. This study aims to utilize dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to identify and compare brain regions with BBBD in patients with epilepsy (PWE) and healthy individuals., Methods: We scanned 50 drug-resistant epilepsy (DRE) patients and 58 control participants from four global specialized epilepsy centers using DCE-MRI. The presence and extent of BBBD were analyzed and compared between PWE and healthy controls., Results: Both greater brain volume and higher number of brain regions with BBBD were significantly present in PWE compared to healthy controls (p < 10 -7 ). No differences in total brain volume with BBBD were observed in patients diagnosed with either focal seizures or generalized epilepsy, despite variations in the affected regions. Overall brain volume with BBBD did not differ in PWE with MRI-visible lesions compared with non-lesional cases. BBBD was observed in brain regions suspected to be related to the onset of seizures in 82% of patients (n = 39) and was typically identified in, adjacent to, and/or in the same hemisphere as the suspected epileptogenic lesion (n = 10)., Significance: These findings are consistent with pre-clinical studies that highlight the role of BBBD in the development of DRE and identify microvascular stabilization as a potential therapeutic strategy., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Published: 2024
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30. Focal, generalised epilepsy or both?

Author: Neligan A, Vivekananda U, and Sander JW
Abstract: A 29-year-old woman presented with a witnessed convulsion, with semiology consistent with a focal-to-bilateral tonic-clonic seizure. Routine EEG supported a syndromic diagnosis of idiopathic generalised epilepsy with photosensitivity. We discuss the clinical utility of seizure semiology, highlighting the caveat that over-reliance or sole reliance on the ictal semiology may result in an erroneous diagnosis of focal epilepsy in someone with a generalised epilepsy., Competing Interests: Competing interests: AN and UV have no conflicts of interest. JWS reports grants and personal fees from UCB, grants from NIHR and Angelini, and personal fees from UCB and Angelini, outside the submitted work., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2024
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31. Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Author: García-Marín LM, Campos AI, Diaz-Torres S, Rabinowitz JA, Ceja Z, Mitchell BL, Grasby KL, Thorp JG, Agartz I, Alhusaini S, Ames D, Amouyel P, Andreassen OA, Arfanakis K, Arias-Vasquez A, Armstrong NJ, Athanasiu L, Bastin ME, Beiser AS, Bennett DA, Bis JC, Boks MPM, Boomsma DI, Brodaty H, Brouwer RM, Buitelaar JK, Burkhardt R, Cahn W, Calhoun VD, Carmichael OT, Chakravarty M, Chen Q, Ching CRK, Cichon S, Crespo-Facorro B, Crivello F, Dale AM, Smith GD, de Geus EJC, De Jager PL, de Zubicaray GI, Debette S, DeCarli C, Depondt C, Desrivières S, Djurovic S, Ehrlich S, Erk S, Espeseth T, Fernández G, Filippi I, Fisher SE, Fleischman DA, Fletcher E, Fornage M, Forstner AJ, Francks C, Franke B, Ge T, Goldman AL, Grabe HJ, Green RC, Grimm O, Groenewold NA, Gruber O, Gudnason V, Håberg AK, Haukvik UK, Heinz A, Hibar DP, Hilal S, Himali JJ, Ho BC, Hoehn DF, Hoekstra PJ, Hofer E, Hoffmann W, Holmes AJ, Homuth G, Hosten N, Ikram MK, Ipser JC, Jack CR Jr, Jahanshad N, Jönsson EG, Kahn RS, Kanai R, Klein M, Knol MJ, Launer LJ, Lawrie SM, Hellard SL, Lee PH, Lemaître H, Li S, Liewald DCM, Lin H, Longstreth WT Jr, Lopez OL, Luciano M, Maillard P, Marquand AF, Martin NG, Martinot JL, Mather KA, Mattay VS, McMahon KL, Mecocci P, Melle I, Meyer-Lindenberg A, Mirza-Schreiber N, Milaneschi Y, Mosley TH, Mühleisen TW, Müller-Myhsok B, Maniega SM, Nauck M, Nho K, Niessen WJ, Nöthen MM, Nyquist PA, Oosterlaan J, Pandolfo M, Paus T, Pausova Z, Penninx BWJH, Pike GB, Psaty BM, Pütz B, Reppermund S, Rietschel MD, Risacher SL, Romanczuk-Seiferth N, Romero-Garcia R, Roshchupkin GV, Rotter JI, Sachdev PS, Sämann PG, Saremi A, Sargurupremraj M, Saykin AJ, Schmaal L, Schmidt H, Schmidt R, Schofield PR, Scholz M, Schumann G, Schwarz E, Shen L, Shin J, Sisodiya SM, Smith AV, Smoller JW, Soininen HS, Steen VM, Stein DJ, Stein JL, Thomopoulos SI, Toga AW, Tordesillas-Gutiérrez D, Trollor JN, Valdes-Hernandez MC, van T Ent D, van Bokhoven H, van der Meer D, van der Wee NJA, Vázquez-Bourgon J, Veltman DJ, Vernooij MW, Villringer A, Vinke LN, Völzke H, Walter H, Wardlaw JM, Weinberger DR, Weiner MW, Wen W, Westlye LT, Westman E, White T, Witte AV, Wolf C, Yang J, Zwiers MP, Ikram MA, Seshadri S, Thompson PM, Satizabal CL, Medland SE, and Rentería ME
Subjects: Humans, Female, Male, Organ Size genetics, Attention Deficit Disorder with Hyperactivity genetics, Attention Deficit Disorder with Hyperactivity pathology, Parkinson Disease genetics, Parkinson Disease pathology, Polymorphism, Single Nucleotide, Genomics methods, Adult, Genetic Predisposition to Disease, Middle Aged, White People genetics, Genome-Wide Association Study, Multifactorial Inheritance genetics, Brain pathology
Abstract: Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2024
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32. The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives.

Author: Specchio N, Trivisano M, Aronica E, Balestrini S, Arzimanoglou A, Colasante G, Cross JH, Jozwiak S, Wilmshurst JM, Vigevano F, Auvin S, Nabbout R, and Curatolo P
Subjects: Humans, Genetic Testing, Genetic Therapy, Epilepsy genetics
Abstract: Recent advances in genetic testing technologies have revolutionised the identification of genetic abnormalities in early onset developmental and epileptic encephalopathies (DEEs). In this Review, we provide an update on the expanding landscape of genetic factors contributing to DEEs, encompassing over 800 reported genes. We focus on the cellular and molecular mechanisms driving epileptogenesis, with an emphasis on emerging therapeutic strategies and effective treatment options. We explore noteworthy, novel genes linked to DEE phenotypes, such as gBRAT-1 and GNAO1, and gene families such as GRIN and HCN. Understanding the network-level effects of gene variants will pave the way for potential gene therapy applications. Given the diverse comorbidities associated with DEEs, a multidisciplinary team approach is essential. Despite ongoing efforts and improved genetic testing, DEEs lack a cure, and treatment complexities persist. This Review underscores the necessity for larger international prospective studies focusing on both seizure outcomes and developmental trajectories., Competing Interests: Declaration of interests NS has served on scientific advisory boards for GW Pharma, BioMarin, Arvelle, Marinus, and Takeda; has received speaker honoraria from Eisai, BioMarin, Livanova, Sanofi; and has served as an investigator for Zogenix, Marinus, BioMarin, Union Chimique Belge (UCB), and Roche. MT has served on advisory boards for BioMarin and Biocodex; has received speaker honoraria from BioMarin, Biocodex, and Orion; and has served as an investigator for Zogenix, Marinus, BioMarin, UCB, and Roche. SB has served on advisory boards for Biocodex and has received speaker and consultant honoraria from Angelini, Biocodex, and Jazz Pharmaceutics. AA has received speaker and consultant honoraria from Biocodex, EISAI, Jazz Pharmaceutics, Sanofi, and UCB and is co-director of the European Consortium for Epilepsy Trials. JHC has received grants from Stoke Therapeutics, Ultragenyx, UCB, the National Institute for Health and Care Research, Great Ormond Street Hospital Children's Charity, LifeARC, the Waterloo Foundation, and Action Medical Research. JHC has also received honoraria payments from Biocodex, Nutricia, Jazz Pharmaceuticals, Nutricia, Takeda, and UCB, all of which have been paid to University College London. JMW is associate editor of Epilepsia and chief editor of the Paediatric Neurology subsection of Frontiers in Neurology and has served on advisory boards for Sanofi and Novartis. FV has received speaker fees from Zogenix, Neuraxpharm, Angelini, and Eisai and has served on advisory boards for Zogenix, Neuraxpharm, Angelini, and Eisai. SA has received honoraria for lectures from Biocodex, BioMarin, Eisai, Jazz Pharmaceuticals, Neuraxpharm, Nutricia, Stoke, UCB, and Zogenix; has been paid as a consultant for lectures by Biocodex, Encoded, Grintherapeutics, Jazz Pharmaceuticals, Neuraxpharm, Nutricia, Orion, Proveca, Supernus, Stoke, Takeda, UCB, and Xenon; and has been an investigator for clinical trials for Eisai, Proveca, Takeda, and UCB. RN has served as principal investigator in clinical trials for Novartis, Nutricia, Eisai, UCB, GW Pharma, and Livanova; has received consulting and lecturer honoraria from BioGene, BioMarin, Praxis, GW Pharma, Zogenix, Novartis, Nutricia, Stoke, Ionis, Targeon, Neuraxpharma, Takeda, Nutricia, Biocodex, Advicennes, and Eisai; and has received unrestricted research grants from Eisai, UCB, Livanova, and GW Pharma and academic research grants from the European Joint Programme on Rare Diseases (Horizons 2020). PC has served on a scientific advisory board for Novartis, has received speaker honoraria from Jazz Pharmaceuticals and ItalFarmaco, and has served as investigator for clinical trials for Novartis. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)
Published: 2024
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33. Circulating microRNAs and isomiRs as biomarkers for the initial insult and epileptogenesis in four experimental epilepsy models: The EPITARGET study.

Author: van Vliet EA, Scheper M, Mills JD, Puhakka N, Szydlowska K, Ferracin M, Lovisari F, Soukupova M, Zucchini S, Srivastava PK, Johnson MR, Lukasiuk K, Gorter JA, Aronica E, Pitkänen A, and Simonato M
Subjects: Animals, Rats, Male, Electroencephalography, MicroRNAs blood, MicroRNAs genetics, Rats, Sprague-Dawley, Kainic Acid, Epilepsy blood, Epilepsy genetics, Disease Models, Animal, Biomarkers blood, Circulating MicroRNA blood, Circulating MicroRNA genetics
Abstract: Objective: Structural epilepsies can manifest months or years after the occurrence of an initial epileptogenic insult, making them amenable for secondary prevention. However, development of preventive treatments has been challenged by a lack of biomarkers for identifying the subset of individuals with the highest risk of epilepsy after the epileptogenic insult., Methods: Four different rat models of epileptogenesis were investigated to identify differentially expressed circulating microRNA (miRNA) and isomiR profiles as biomarkers for epileptogenesis. Plasma samples were collected on day 2 and day 9 during the latency period from animals that did or did not develop epilepsy during long-term video-electroencephalographic monitoring. miRNAs and isomiRs were identified and measured in an unsupervised manner, using a genome-wide small RNA sequencing platform. Receiver operating characteristic analysis was performed to determine the performance of putative biomarkers., Results: Two days after an epileptogenic insult, alterations in the levels of several plasma miRNAs and isomiRs predicted epileptogenesis in a model-specific manner. One miRNA, miR-3085, showed good sensitivity (but low specificity) as a prognostic biomarker for epileptogenesis in all four models (area under the curve = .729, sensitivity = 83%, specificity = 64%, p < .05)., Significance: Identified plasma miRNAs and isomiRs are mostly etiology-specific rather than common prognostic biomarkers of epileptogenesis. These data imply that in preclinical and clinical studies, it may be necessary to identify specific biomarkers for different epilepsy etiologies. Importantly, circulating miRNAs like miR-3085 with high negative predictive value for epileptogenesis in different etiologies could be useful candidates for initial screening purposes of epileptogenesis risk., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Published: 2024
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34. WONOEP appraisal: Genetic insights into early onset epilepsies.

Author: Quatraccioni A, Cases-Cunillera S, Balagura G, Coleman M, Rossini L, Mills JD, Casillas-Espinosa PM, Moshé SL, Sankar R, Baulac S, Noebels JL, Auvin S, O'Brien TJ, Henshall DC, Akman Ö, and Galanopoulou AS
Subjects: Humans, Infant, Infant, Newborn, Epilepsy genetics, Epilepsy diagnosis, Age of Onset
Abstract: Early onset epilepsies occur in newborns and infants, and to date, genetic aberrations and variants have been identified in approximately one quarter of all patients. With technological sequencing advances and ongoing research, the genetic diagnostic yield for specific seizure disorders and epilepsies is expected to increase. Genetic variants associated with epilepsy include chromosomal abnormalities and rearrangements of various sizes as well as single gene variants. Among these variants, a distinction can be made between germline and somatic, with the latter being increasingly identified in epilepsies with focal cortical malformations in recent years. The identification of the underlying genetic mechanisms of epilepsy syndromes not only revolutionizes the diagnostic schemes but also leads to a better understanding of the diseases and their interrelationships, ultimately providing new opportunities for therapeutic targeting. At the XVI Workshop on Neurobiology of Epilepsy (WONOEP 2022, Talloires, France, July 2022), various etiologies, research models, and mechanisms of genetic early onset epilepsies were presented and discussed., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Published: 2024
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35. N-of-1 trials in epilepsy: A systematic review and lessons paving the way forward.

Author: Defelippe VM, Brilstra EH, Otte WM, Cross HJ, O'Callaghan F, De Giorgis V, Poduri A, Lerche H, Sisodiya S, Braun KPJ, Jansen FE, and Perucca E
Subjects: Humans, Anticonvulsants therapeutic use, Clinical Trials as Topic methods, Randomized Controlled Trials as Topic methods, Research Design, Epilepsy drug therapy, Epilepsy therapy, Cross-Over Studies
Abstract: Objective: Defined as prospective single-patient crossover studies with repeated paired cycles of active and control intervention, N-of-1 trials have gained attention as an option to obtain high-quality evidence of efficacy, particularly for patients with rare epilepsies in whom conduction of well-powered randomized controlled trials can be challenging. The objective of this systematic review is to provide an appraisal of the literature on N-of-1 trials in individuals with epilepsy., Methods: We searched PubMed and Embase on January 12, 2024, for studies meeting the following criteria: prospectively planned, within-patient, multiple-crossover design in individuals with epilepsy and outcomes related to comorbidities. Information on design, outcome measurements, intervention, and analyses was retrieved. Risk of bias assessment was performed using the Risk of Bias in N-of-1 Trials (RoBiNT) scale. We highlighted methodological aspects of the N-of-1 trials identified and discuss future recommendations., Results: Five studies met our inclusion criteria. An additional multiple-crossover trial that evaluated treatment effects exclusively at group level was also included because of its relevance to N-of-1 study methodology. The studies enrolled individuals with focal seizures, absences or cognitive impairement and electrographic discharges. Treatments included established or investigational antiseizure medications, off-label medications, neurostimulation or lifestyle intervention. Three of the five N-of-1 trials reported on individual cases. The studies' strengths were the use of individualized treatment dosages and symptom-specific patient-reported outcomes. Limitations were related to minimal reporting of baseline characteristics and seizure burden., Significance: The trials identified by our search exemplify how the N-of-1 design can be applied to assess interventions in individuals with epilepsy-related disorders. Future N-of-1 trials of antiseizure interventions should take into account baseline seizure frequency, should apply statistical models suited to capture seizure frequency changes reliably and make predefined interim assessments. Non-seizure outcome measures evaluable over short periods should be considered. Tailored N-of-1 methodology could pave the way to evidence-based, treatment selection for patients with rare epilepsies., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Published: 2024
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36. Nonictal electroencephalographic measures for the diagnosis of functional seizures.

Author: Hinchliffe CHL, Yogarajah M, Elkommos S, Tang H, and Abasolo D
Subjects: Humans, Male, Female, Adult, Middle Aged, Young Adult, Support Vector Machine, Epilepsy diagnosis, Epilepsy physiopathology, Electroencephalography methods, Seizures diagnosis, Seizures physiopathology, Machine Learning
Abstract: Objective: Functional seizures (FS) look like epileptic seizures but are characterized by a lack of epileptic activity in the brain. Approximately one in five referrals to epilepsy clinics are diagnosed with this condition. FS are diagnosed by recording a seizure using video-electroencephalography (EEG), from which an expert inspects the semiology and the EEG. However, this method can be expensive and inaccessible and can present significant patient burden. No single biomarker has been found to diagnose FS. However, the current limitations in FS diagnosis could be improved with machine learning to classify signal features extracted from EEG, thus providing a potentially very useful aid to clinicians., Methods: The current study has investigated the use of seizure-free EEG signals with machine learning to identify subjects with FS from those with epilepsy. The dataset included interictal and preictal EEG recordings from 48 subjects with FS (mean age = 34.76 ± 10.55 years, 14 males) and 29 subjects with epilepsy (mean age = 38.95 ± 13.93 years, 18 males) from which various statistical, temporal, and spectral features from the five EEG frequency bands were extracted then analyzed with threshold accuracy, five machine learning classifiers, and two feature importance approaches., Results: The highest classification accuracy reported from thresholding was 60.67%. However, the temporal features were the best performing, with the highest balanced accuracy reported by the machine learning models: 95.71% with all frequency bands combined and a support vector machine classifier., Significance: Machine learning was much more effective than using individual features and could be a powerful aid in FS diagnosis. Furthermore, combining the frequency bands improved the accuracy of the classifiers in most cases, and the lowest performing EEG bands were consistently delta and gamma., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Published: 2024
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37. Neuromodulation with Transcranial Magnetic Stimulation in Epilepsia Partialis Continua: Scoping review and clinical experience.

Author: Velasco-Mérida M, Lázaro M, Duncan JS, Alarcon G, Stavropoulos I, and Valentín A
Abstract: Introduction: Epilepsia Partialis Continua (EPC) is a challenging condition in which repetitive transcranial magnetic stimulation (rTMS) can induce a neuromodulation effect of potential diagnostic and therapeutic value., Methods: A comprehensive literature search was conducted using Pubmed and Web of Science databases to identify cases of EPC who underwent rTMS, including children and adults. Additionally, we present two patients from our centre who underwent rTMS at a low frequency (0.5 Hz) with simultaneous EEG recording with the aim of assessing potential improvement in seizure frequency and severity., Results: Eight articles were selected comprising 16 patients (15 with EPC and one with continuous myoclonia). In three of these patients, no clinical or EEG changes were noted; the remaining cases showed transitory clinical improvements. We report two patients with EPC, in whom low frequency rTMS was associated with transient reduction in frequency and severity of seizures and improvements in hand function and dexterity. In one of these cases, rTMS suggested a potential target for intracranial recordings, subacute cortical stimulation and localised resection., Conclusion: In selected patients with EPC, rTMS can be used as a potential diagnostic and therapeutic tool., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest regarding the publication of this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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38. Drug repurposing in status epilepticus.

Author: Walker MC
Abstract: The treatment of status epilepticus (SE) has changed little in the last 20 years, largely because of the high risks and costs of new drug development for SE. Moreover, SE poses specific challenges to drug development, such as patient diversity, logistical hurdles, and the need for acute treatment strategies that differ from chronic seizure prevention. This has reduced the appetite of industry to develop new drugs in this area. Drug repurposing is an attractive approach to address this unmet need. It offers significant advantages, including reduced development time, lower costs, and higher success rates, compared to novel drug development. Here I demonstrate how novel methods integrating biological knowledge and computational methods can be applied to drug repurposing in status epilepticus. Biological approaches focus on addressing mechanisms underlying drug resistance in SE (using for example ketamine, tacrolimus and safinamide) and longer-term consequences (using for example omaveloxolone, celecoxib and losartan). Additionally, artificial intelligence platforms, such as ChatGPT, can rapidly generate promising drug lists, while in silico methods can analyze gene expression changes to predict molecular targets. Combining AI and in silico approaches has identified several candidate drugs, including metformin, sirolimus and riluzole, for SE treatment. Despite the promise of repurposing, challenges remain, such as intellectual property issues and regulatory barriers. Nonetheless, drug repurposing presents a viable solution to the high costs and slow progress of traditional drug development for SE. This paper is based on a presentation made at the 9th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures, in April 2024., Competing Interests: Declaration of competing interest MCW has received honoraria or consulting fees from Bioquest, Eisai, UCB pharma, Angelini, Seer and EpilepsyGtx. MCW has shares in EpilpesyGtx, an epilepsy gene therapy company., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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39. Big data research is everyone's research-Making epilepsy data science accessible to the global community: Report of the ILAE big data commission.

Author: Josephson CB, Aronica E, Beniczky S, Boyce D, Cavalleri G, Denaxas S, French J, Jehi L, Koh H, Kwan P, McDonald C, Mitchell JW, Rampp S, Sadleir L, Sisodiya SM, Wang I, Wiebe S, Yasuda C, and Youngerman B
Abstract: Epilepsy care generates multiple sources of high-dimensional data, including clinical, imaging, electroencephalographic, genomic, and neuropsychological information, that are collected routinely to establish the diagnosis and guide management. Thanks to high-performance computing, sophisticated graphics processing units, and advanced analytics, we are now on the cusp of being able to use these data to significantly improve individualized care for people with epilepsy. Despite this, many clinicians, health care providers, and people with epilepsy are apprehensive about implementing Big Data and accompanying technologies such as artificial intelligence (AI). Practical, ethical, privacy, and climate issues represent real and enduring concerns that have yet to be completely resolved. Similarly, Big Data and AI-related biases have the potential to exacerbate local and global disparities. These are highly germane concerns to the field of epilepsy, given its high burden in developing nations and areas of socioeconomic deprivation. This educational paper from the International League Against Epilepsy's (ILAE) Big Data Commission aims to help clinicians caring for people with epilepsy become familiar with how Big Data is collected and processed, how they are applied to studies using AI, and outline the immense potential positive impact Big Data can have on diagnosis and management., (© 2024 The Author(s). Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Published: 2024
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40. Are High-Frequency Activities Reliable Biomarkers of the FCDII Lesion?

Author: Padmasola GP and Lignani G
Published: 2024
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41. Early developmental alterations of CA1 pyramidal cells in Dravet syndrome.

Author: Jones SP, O'Neill N, Carpenter JC, Muggeo S, Colasante G, Kullmann DM, and Lignani G
Subjects: Animals, Mice, Disease Models, Animal, Male, Mice, Transgenic, Neuronal Plasticity physiology, Neuronal Plasticity genetics, Mice, Inbred C57BL, Pyramidal Cells metabolism, Pyramidal Cells pathology, Epilepsies, Myoclonic genetics, Epilepsies, Myoclonic pathology, NAV1.1 Voltage-Gated Sodium Channel genetics, CA1 Region, Hippocampal metabolism, CA1 Region, Hippocampal pathology
Abstract: Dravet Syndrome (DS) is most often caused by heterozygous loss-of-function mutations in the voltage-gated sodium channel gene SCN1A (Na v 1.1), resulting in severe epilepsy and neurodevelopmental impairment thought to be cause by reduced interneuron excitability. However, recent studies in mouse models suggest that interneuron dysfunction alone does not completely explain all the cellular and network impairments seen in DS. Here, we investigated the development of the intrinsic, synaptic, and network properties of CA1 pyramidal cells in a DS model prior to the appearance of overt seizures. We report that CA1 pyramidal cell development is altered by heterozygous reduction of Scn1a, and propose that this is explained by a period of reduced intrinsic excitability in early postnatal life, during which Scn1a is normally expressed in hippocampal pyramidal cells. We also use a novel ex vivo model of homeostatic plasticity to show an instability in homeostatic response during DS epileptogenesis. This study provides evidence for the early effects of Scn1a haploinsufficiency in pyramidal cells in contributing to the pathophysiology of DS., Competing Interests: Declaration of competing interest No conflicts to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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42. Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and Vici syndrome patients.

Author: Deneubourg C, Salimi Dafsari H, Lowe S, Martinez-Cotrina A, Mazaud D, Park SH, Vergani V, Almacellas Barbanoj A, Maroofian R, Averdunk L, Ghayoor-Karimiani E, Jayawant S, Mignot C, Keren B, Peters R, Kamath A, Mattas L, Verma S, Silwal A, Distelmaier F, Houlden H, Lignani G, Antebi A, Jepson J, Jungbluth H, and Fanto M
Abstract: Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 ( EPG5 ) gene that is crucial for autophagosome-lysosome fusion and autophagic clearance. Here, we used Drosophila melanogaster to study the importance of Epg5 in development, aging, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions. Abbreviations : AD: Alzheimer's disease; ALS-FTD: Amyotrophic Lateral Sclerosis-FrontoTemoporal Dementia; DART: Drosophila Arousal Tracking; ECoG: electrocorticogram; EEG: electroencephalogram; EPG5 : ectopic P-granules 5 autophagy tethering factor; KA: kainic acid; MBs: mushroom bodies; MRI magnetic resonance imaging; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson's disease; TSC : TSC complex; VS: Vici syndrome.
Published: 2024
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43. Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline.

Author: Liu J, Binding L, Puntambekar I, Patodia S, Lim YM, Mryzyglod A, Xiao F, Pan S, Mito R, de Tisi J, Duncan JS, Baxendale S, Koepp M, and Thom M
Subjects: Humans, Male, Female, Adult, Middle Aged, White Matter pathology, White Matter diagnostic imaging, Young Adult, Cognitive Dysfunction pathology, Cognitive Dysfunction diagnostic imaging, Cognitive Dysfunction etiology, Cognition Disorders etiology, Cognition Disorders diagnostic imaging, Cognition Disorders pathology, Hippocampus pathology, Hippocampus diagnostic imaging, Epilepsy, Temporal Lobe pathology, Epilepsy, Temporal Lobe diagnostic imaging, Diffusion Magnetic Resonance Imaging
Abstract: White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05-0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE., (© 2024. The Author(s).)
Published: 2024
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44. Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). I. Drugs in preclinical and early clinical development.

Author: Bialer M, Johannessen SI, Koepp MJ, Perucca E, Perucca P, Tomson T, and White HS
Subjects: Animals, Humans, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Congresses as Topic, Drug Development methods, Drug Evaluation, Preclinical, Anticonvulsants pharmacology, Anticonvulsants therapeutic use, Epilepsy drug therapy, Epilepsy genetics, Seizures drug therapy, Seizures genetics
Abstract: For >30 years, the Eilat Conference on New Antiepileptic Drugs and Devices has provided a forum for the discussion of advances in the development of new therapies for seizures and epilepsy. The EILAT XVII conference took place in Madrid, Spain, on May 5-8, 2024. Participants included basic scientists and clinical investigators from industry and academia, other health care professionals, and representatives from lay organizations. We summarize in this article information on treatments in preclinical and in early clinical development discussed at the conference. These include AMT-260, a gene therapy designed to downregulate the expression of Glu2K subunits of kainate receptors, in development for the treatment of drug-resistant seizures associated with mesial temporal sclerosis; BHV-7000, a selective activator of heteromeric Kv7.2/7.3 potassium channels, in development for the treatment of focal epilepsy; ETX101, a recombinant adeno-associated virus serotype 9 designed to increase Na V 1.1 channel density in inhibitory γ-aminobutyric acidergic (GABAergic) neurons, in development for the treatment of SCN1A-positive Dravet syndrome; GAO-3-02, a compound structurally related to synaptamide, which exerts antiseizure activity at least in part through an action on cannabinoid type 2 receptors; LRP-661, a structural analogue of cannabidiol, in development for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex; OV329, a selective inactivator of GABA aminotransferase, in development for the treatment of drug-resistant seizures; PRAX-628, a functionally selective potent sodium channel modulator with preference for the hyperexcitable state of sodium channels, in development for the treatment of focal seizures; RAP-219, a selective negative allosteric modulator of transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor regulatory protein γ-8, in development for the treatment of focal seizures; and rozanolixizumab, a humanized anti-neonatal Fc receptor monoclonal antibody, in development for the treatment of LGI1 autoimmune encephalitis. Treatments in more advanced development are summarized in Part II of this report., (© 2024 International League Against Epilepsy.)
Published: 2024
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45. Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development.

Author: Bialer M, Johannessen SI, Koepp MJ, Perucca E, Perucca P, Tomson T, and White HS
Subjects: Humans, Drug Development, Drugs, Investigational therapeutic use, Animals, Anticonvulsants therapeutic use, Epilepsy drug therapy, Epilepsy genetics, Seizures drug therapy
Abstract: The 17th Eilat Conference on New Antiepileptic Drugs and Devices took place in Madrid, Spain on May 5-8, 2024. As usual, the core part of the conference consisted of presentations on investigational drugs at various stages of development for epilepsy-related indications. Summaries of information on compounds in preclinical or early clinical development are included in an accompanying publication (Part I). In this article, we provide summaries for five compounds in more advanced clinical development, i.e. compounds for which some information on antiseizure activity in individuals with epilepsy is available. These investigational treatments include azetukalner (XEN1101), a potent, K V 7.2/7.3-specific potassium channel opener in development for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5-HT 2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit-containing N-methyl-D-aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain-of-function mutations in the GRIN1, -2A, -2B, or -2D genes; soticlestat (TAK-935), a selective inhibitor of cholesterol 24-hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome; and STK-001, an antisense oligonucleotide designed to upregulate Na v 1.1 protein expression and improve outcomes in individuals with Dravet syndrome. The diversity in mechanisms of action of these agents illustrates different approaches being pursued in the discovery of novel treatments for seizures and epilepsy. For two of the compounds discussed in this report (azetukalner and soticlestat), clinical evidence of efficacy has already been obtained in a randomized placebo-controlled adjunctive-therapy trial. For the other compounds, adequately powered placebo-controlled efficacy trials have not been completed to date., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Published: 2024
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46. Italian report on RARE epilepsies (i-RARE): A consensus on multidisciplinarity.

Author: Riva A, Coppola A, Bisulli F, Verrotti A, Bagnasco I, Elia M, Darra F, Lattanzi S, Meletti S, La Neve A, Di Gennaro G, Brambilla I, Santoro K, Prisco T, Macari F, Gambardella A, di Bonaventura C, Balestrini S, Marini C, Pruna D, Capovilla G, Specchio N, Gobbi G, and Striano P
Subjects: Humans, Italy, Epilepsy therapy, Consensus, Delphi Technique, Rare Diseases therapy
Abstract: Objective: Rare and complex epilepsies encompass a diverse range of disorders characterized by seizures. We aimed to establish a consensus on key issues related to these conditions through collaboration among experienced neurologists, neuropediatricians, and patient advocacy representatives., Methods: Employing a modified Delphi method, a scientific board comprising 20 physicians and 4 patient advocacy representatives synthesized existing literature with their expertise to formulate statements on contentious topics. A final 32-member expert panel, representing diverse regions of Italy, validated these statements through a two-round voting process, with consensus defined as an average score ≥7., Results: Sixteen statements reached a consensus, emphasizing the necessity for epidemiological studies to ascertain the true prevalence of rare epilepsies. Etiology emerged as a crucial factor influencing therapeutic strategies and outcome prediction, with particular concern regarding prolonged and tonic-clonic seizures. The importance of early implementation of specific drugs and non-pharmacological interventions in the treatment algorithm for developmental and epileptic encephalopathies (DEEs) was underscored. Multidisciplinary care involving experts with diverse skills was deemed essential, emphasizing non-seizure outcomes in adolescence and adulthood., Significance: This national consensus underscores the imperative for personalized, comprehensive, and multidisciplinary management of rare epilepsies/DEEs. It advocates for increased research, particularly in epidemiology and therapeutic approaches, to inform clinical decision-making and healthcare policies, ultimately enhancing patients' outcomes., Plain Language Summary: The modified Delphi method is broadly used to evaluate debated topics. In this work, we sought the consensus on integrated and social care in epilepsy management. Both representatives of high-level epilepsy centers and patients' caregivers were directly involved., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Published: 2024
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47. Attitudes and perceptions towards epilepsy in an onchocerciasis-endemic region of Tanzania: a mixed approach to determine the magnitude and driving factors.

Author: Mushi VP, Kidima W, Massawe IS, Magili PF, Bhwana D, Kaaya RE, Kimambo H, Hyera HF, Matuja W, Sen A, Sander JW, Colebunders R, Mahone S, Newton CR, and Mmbando BP
Subjects: Humans, Tanzania epidemiology, Female, Male, Adult, Cross-Sectional Studies, Middle Aged, Surveys and Questionnaires, Social Stigma, Young Adult, Endemic Diseases, Adolescent, Qualitative Research, Epilepsy psychology, Epilepsy epidemiology, Health Knowledge, Attitudes, Practice, Onchocerciasis psychology, Onchocerciasis epidemiology, Focus Groups
Abstract: Background: Epilepsy remains a significant public health concern in Tanzania, with affected individuals enduring stigma, whether through actions or perceptions. Myths, misunderstandings, and misconceptions about epilepsy have persisted due to a multitude of factors. Here, we assessed attitudes and perceptions toward epilepsy in Mahenge., Methods: A cross-sectional study utilising a mixed-methods approach was undertaken in eight villages in the Ulanga district of Mahenge, integrating a semi-structured questionnaire and focus group discussions (FGDs). The questionnaire involved 778 community members, and 15 FGDs were conducted (seven groups with people with epilepsy and eight without). Descriptive statistics, chi-square, and logistic regression were used for quantitative analysis, while we used NVivo version 14 for thematic analysis of qualitative data., Results: Of 778 participants, over half were women (425, 54.6%) with a median age of 41 years (IQR: 30-55) and most had completed primary education (79.9%). The majority of participants were aware of epilepsy (96.8%), yet they displayed low knowledge (51%), negative attitudes (45.5%), and perceptions (42.1%) towards the disorder. A low level of understanding was significantly associated with negative attitudes (Adjusted Odds Ratio [AOR] = 1.89, 95%CI: 1.41-2.53) and perceptions (AOR = 3.22, 95%CI: 2.05-5.04) towards epilepsy. In the qualitative analysis, often hereditary factors and infections were named as causes of epilepsy, along with misconceptions involving witchcraft and divine punishment. There was also a misconception about the contagiousness of epilepsy. Traditional healers were often the initial point of treatment. Epilepsy-related stigma was evident, with individuals with epilepsy facing derogatory labels, social isolation, and barriers to education. Lastly, there was a lack of understanding regarding a possible association between epilepsy and onchocerciasis., Conclusions: Despite high awareness of epilepsy, there is insufficient understanding, negative attitudes, and perceptions, including misconceptions and stigma about this neurologic condition. Community-based education programmes are essential for promoting proper healthcare-seeking behaviour and dispelling myths., (© 2024. The Author(s).)
Published: 2024
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48. Neuronal oscillations in cognition: Down syndrome as a model of mouse to human translation.

Author: Chang P, Pérez-González M, Constable J, Bush D, Cleverley K, Tybulewicz VLJ, Fisher EMC, and Walker MC
Abstract: Down syndrome (DS), a prevalent cognitive disorder resulting from trisomy of human chromosome 21 (Hsa21), poses a significant global health concern. Affecting approximately 1 in 800 live births worldwide, DS is the leading genetic cause of intellectual disability and a major predisposing factor for early-onset Alzheimer's dementia. The estimated global population of individuals with DS is 6 million, with increasing prevalence due to advances in DS health care. Global efforts are dedicated to unraveling the mechanisms behind the varied clinical outcomes in DS. Recent studies on DS mouse models reveal disrupted neuronal circuits, providing insights into DS pathologies. Yet, translating these findings to humans faces challenges due to limited systematic electrophysiological analyses directly comparing human and mouse. Additionally, disparities in experimental procedures between the two species pose hurdles to successful translation. This review provides a concise overview of neuronal oscillations in human and rodent cognition. Focusing on recent DS mouse model studies, we highlight disruptions in associated brain function. We discuss various electrophysiological paradigms and suggest avenues for exploring molecular dysfunctions contributing to DS-related cognitive impairments. Deciphering neuronal oscillation intricacies holds promise for targeted therapies to alleviate cognitive disabilities in DS individuals., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Published: 2024
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49. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Author: Chen S, Abou-Khalil BW, Afawi Z, Ali QZ, Amadori E, Anderson A, Anderson J, Andrade DM, Annesi G, Arslan M, Auce P, Bahlo M, Baker MD, Balagura G, Balestrini S, Banks E, Barba C, Barboza K, Bartolomei F, Bass N, Baum LW, Baumgartner TH, Baykan B, Bebek N, Becker F, Bennett CA, Beydoun A, Bianchini C, Bisulli F, Blackwood D, Blatt I, Borggräfe I, Bosselmann C, Braatz V, Brand H, Brockmann K, Buono RJ, Busch RM, Caglayan SH, Canafoglia L, Canavati C, Castellotti B, Cavalleri GL, Cerrato F, Chassoux F, Cherian C, Cherny SS, Cheung CL, Chou IJ, Chung SK, Churchhouse C, Ciullo V, Clark PO, Cole AJ, Cosico M, Cossette P, Cotsapas C, Cusick C, Daly MJ, Davis LK, Jonghe P, Delanty N, Dennig D, Depondt C, Derambure P, Devinsky O, Di Vito L, Dickerson F, Dlugos DJ, Doccini V, Doherty CP, El-Naggar H, Ellis CA, Epstein L, Evans M, Faucon A, Feng YA, Ferguson L, Ferraro TN, Da Silva IF, Ferri L, Feucht M, Fields MC, Fitzgerald M, Fonferko-Shadrach B, Fortunato F, Franceschetti S, French JA, Freri E, Fu JM, Gabriel S, Gagliardi M, Gambardella A, Gauthier L, Giangregorio T, Gili T, Glauser TA, Goldberg E, Goldman A, Goldstein DB, Granata T, Grant R, Greenberg DA, Guerrini R, Gundogdu-Eken A, Gupta N, Haas K, Hakonarson H, Haryanyan G, Häusler M, Hegde M, Heinzen EL, Helbig I, Hengsbach C, Heyne H, Hirose S, Hirsch E, Ho CJ, Hoeper O, Howrigan DP, Hucks D, Hung PC, Iacomino M, Inoue Y, Inuzuka LM, Ishii A, Jehi L, Johnson MR, Johnstone M, Kälviäinen R, Kanaan M, Kara B, Kariuki SM, Kegele J, Kesim Y, Khoueiry-Zgheib N, Khoury J, King C, Klein KM, Kluger G, Knake S, Kok F, Korczyn AD, Korinthenberg R, Koupparis A, Kousiappa I, Krause R, Krenn M, Krestel H, Krey I, Kunz WS, Kurlemann G, Kuzniecky RI, Kwan P, La Vega-Talbott M, Labate A, Lacey A, Lal D, Laššuthová P, Lauxmann S, Lawthom C, Leech SL, Lehesjoki AE, Lemke JR, Lerche H, Lesca G, Leu C, Lewin N, Lewis-Smith D, Li GH, Liao C, Licchetta L, Lin CH, Lin KL, Linnankivi T, Lo W, Lowenstein DH, Lowther C, Lubbers L, Lui CHT, Macedo-Souza LI, Madeleyn R, Madia F, Magri S, Maillard L, Marcuse L, Marques P, Marson AG, Matthews AG, May P, Mayer T, McArdle W, McCarroll SM, McGoldrick P, McGraw CM, McIntosh A, McQuillan A, Meador KJ, Mei D, Michel V, Millichap JJ, Minardi R, Montomoli M, Mostacci B, Muccioli L, Muhle H, Müller-Schlüter K, Najm IM, Nasreddine W, Neaves S, Neubauer BA, Newton CRJC, Noebels JL, Northstone K, Novod S, O'Brien TJ, Owusu-Agyei S, Özkara Ç, Palotie A, Papacostas SS, Parrini E, Pato C, Pato M, Pendziwiat M, Pennell PB, Petrovski S, Pickrell WO, Pinsky R, Pinto D, Pippucci T, Piras F, Piras F, Poduri A, Pondrelli F, Posthuma D, Powell RHW, Privitera M, Rademacher A, Ragona F, Ramirez-Hamouz B, Rau S, Raynes HR, Rees MI, Regan BM, Reif A, Reinthaler E, Rheims S, Ring SM, Riva A, Rojas E, Rosenow F, Ryvlin P, Saarela A, Sadleir LG, Salman B, Salmon A, Salpietro V, Sammarra I, Scala M, Schachter S, Schaller A, Schankin CJ, Scheffer IE, Schneider N, Schubert-Bast S, Schulze-Bonhage A, Scudieri P, Sedláčková L, Shain C, Sham PC, Shiedley BR, Siena SA, Sills GJ, Sisodiya SM, Smoller JW, Solomonson M, Spalletta G, Sparks KR, Sperling MR, Stamberger H, Steinhoff BJ, Stephani U, Štěrbová K, Stewart WC, Stipa C, Striano P, Strzelczyk A, Surges R, Suzuki T, Talarico M, Talkowski ME, Taneja RS, Tanteles GA, Timonen O, Timpson NJ, Tinuper P, Todaro M, Topaloglu P, Tsai MH, Tumiene B, Turkdogan D, Uğur-İşeri S, Utkus A, Vaidiswaran P, Valton L, van Baalen A, Vari MS, Vetro A, Vlčková M, von Brauchitsch S, von Spiczak S, Wagner RG, Watts N, Weber YG, Weckhuysen S, Widdess-Walsh P, Wiebe S, Wolf SM, Wolff M, Wolking S, Wong I, von Wrede R, Wu D, Yamakawa K, Yapıcı Z, Yis U, Yolken R, Yücesan E, Zagaglia S, Zahnert F, Zara F, Zimprich F, Zizovic M, Zsurka G, Neale BM, and Berkovic SF
Abstract: Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare
Published: 2024
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50. Complicated epilepsy surgery: importance of balancing benefit and deficit.

Author: Duncan JS, Beech V, Chowdhury FA, Miserocchi A, and McEvoy A
Subjects: Humans, Middle Aged, Neurosurgical Procedures methods, Electroencephalography methods, Magnetic Resonance Imaging, Male, Drug Resistant Epilepsy surgery, Drug Resistant Epilepsy diagnostic imaging, Female, Epilepsy surgery, Epilepsy diagnostic imaging
Abstract: The risk-benefit ratio of epilepsy surgery needs careful consideration, is different for each individual and requires a careful, informed dialogue between the person concerned and their medical advisers. We illustrate this process with Virginia, who has had refractory focal epilepsy from age 1 year and a left hemiparesis. At the age of 45 years, we discussed the possibility of epilepsy surgery and went through non-invasive investigations with structural and functional MRI, tractography, scalp video-EEG telemetry, neuropsychological and neuropsychiatric evaluations. This was followed by a decision to carry out intracranial EEG to define the area of seizure onset and its relation to an area of focal cortical dysplasia, eloquent cortex and tracts. We agreed to carry out a focal resection in the knowledge that this would result in a loss of left-hand function. One year later, Virginia is seizure-free on reduced medication. We describe the steps in the process with Virginia's views., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2024
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