Serial Editor Vincent Walsh Institute of Cognitive Neuroscience University College London 17 Queen Square London WC1N 3AR UK Editorial Board Mark Bear, Cambridge, USA Medicine & Translational Neuroscience Hamed Ekhtiari, Tehran, Iran Addiction Hajime Hirase, Wako, Japan Neuronal Microcircuitry Freda Miller, Toronto, Canada Developmental Neurobiology Shane O’Mara, Dublin, Ireland Systems Neuroscience Susan Rossell, Swinburne, Australia Clinical Psychology & Neuropsychiatry Nathalie Rouach, Paris, France Neuroglia Barbara Sahakian, Cambridge, UK Cognition & Neuroethics Bettina Studer, Dusseldorf, Germany Neurorehabilitation Xiao-Jing Wang, New York, USA Computational Neuroscience Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA First edition 2016 Copyright # 2016 Elsevier B.V All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-803886-4 ISSN: 0079-6123 For information on all Elsevier publications visit our website at https://www.elsevier.com/ Publisher: Zoe Kruze Acquisition Editor: Kirsten Shankland Editorial Project Manager: Hannah Colford Production Project Manager: Magesh Kumar Mahalingam Cover Designer: Greg Harris Typeset by SPi Global, India Contributors A Alexander Stanford University, Stanford, CA, United States S.C Baraban Epilepsy Research Laboratory, University of California, San Francisco, CA, United States S Baulac Sorbonne Universit es, UPMC Univ Paris 06, UM 75; INSERM, U1127; CNRS, UMR 7225; ICM (Institut du Cerveau et de la Moelle epinie`re); AP-HP Groupe hospitalier Piti e-Salp^ etrie`re, Paris, France D.A Coulter Perelman School of Medicine, University of Pennsylvania; The Research Institute of the Children’s Hospital of Philadelphia, Philadelphia, PA, United States C.G Dengler Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States J Ghaziri Research Centre, Centre hospitalier de l’Universite de Montreal, Montreal, QC, Canada A Griffin Epilepsy Research Laboratory, University of California, San Francisco, CA, United States F Gu Epilepsy Research Laboratories, Stanford University School of Medicine, Stanford, CA, United States A.E Hernan University of Vermont College of Medicine, Burlington, VT, United States G.L Holmes University of Vermont College of Medicine, Burlington, VT, United States X Jiang Universit e de Montr eal; CHU Ste-Justine Research Center, Montreal, QC, Canada C Krasniak Epilepsy Research Laboratory, University of California, San Francisco, CA, United States M Lachance CHU Ste-Justine Research Center, Montreal, QC, Canada M Maroso Stanford University, Stanford, CA, United States v vi Contributors H.C Mefford University of Washington, Seattle, WA, United States C.T Myers University of Washington, Seattle, WA, United States D.K Nguyen Research Centre, Centre hospitalier de l’Universite de Montreal; CHUM–H^opital Notre-Dame, Montreal, QC, Canada I Parada Epilepsy Research Laboratories, Stanford University School of Medicine, Stanford, CA, United States D.A Prince Epilepsy Research Laboratories, Stanford University School of Medicine, Stanford, CA, United States E Rossignol Universit e de Montr eal; CHU Ste-Justine Research Center, Montreal, QC, Canada I Soltesz Stanford University, Stanford, CA, United States Y Zerouali Research Centre, Centre hospitalier de l’Universite de Montreal; Ecole Polytechnique de Montr eal, Montreal, QC, Canada Preface The following volume stems from a meeting of the same name “The Neurobiology of Epilepsy: From Genes to Networks” held in Montreal on May 4–5, 2015, and organized by Drs L Carmant, P Cossette, E Rossignol, and J.-C Lacaille The editors would like to acknowledge the support of the Groupe de Recherche sur le Syste`me Nerveux Central, Universite de Montreal, for the organization of the meeting Epilepsy is a brain disease caused by abnormal and excessive electrical discharges of neurons The underlying etiologies are multiple, but recent research indicates an important role for pathological genetic variants causing dysregulation of neuronal networks This meeting brought together an international group of clinicians and basic scientists to share new information on the neurobiological basis of epilepsy, including clinical aspects, molecular mechanisms, neuronal networks, as well as animal models and novel therapies By trying to discuss the “neurobiology” of epilepsy, we mean to address the fundamental mechanisms underlying the genetic basis of epilepsy and hopefully lead to an understanding of epilepsy at the molecular, cellular, and network levels that will be translatable into improved treatment for patients with epilepsy The volume begins with sections covering novelties in the clinical investigation of patients with epilepsy Drs Zerouali, Ghaziri, and Nguyen describe multimodal imaging techniques involved in the investigation of epileptic networks in patients, focusing on insular cortex epilepsy Drs Myers and Mefford review current knowledge on the genetic investigation techniques used to identify molecular etiologies in patients with epileptic encephalopathies, and provide an overview of the clinical features and basic mechanisms of recently described genetic epileptic encephalopathies Dr Baulac examines how germline and somatic mutations in the genes of the GATOR1 complex, which regulates the mTOR pathway, cause focal epilepsies with variable foci An understanding of the “neurobiology” of epilepsy must also elucidate seizures at the microcircuit level and understand how neuronal networks are affected in epilepsy The volume continues with three chapters discussing the molecular, cellular, and network mechanisms involved in the genetics of epilepsy Drs Jiang, Lachance, and Rossignol consider the involvement of cortical GABAergic interneuron disorders in genetic causes of epilepsy; Drs Alexander, Maroso, and Soltesz discuss work on the organization and control of epileptic circuits in temporal lobe epilepsy; and Drs Dengler and Coulter review the normal and epilepsy-associated pathologic function of the hippocampal dentate gyrus A major justification for elucidating the genetic, molecular, cellular, and network basis of epilepsies is to develop effective treatment therapies for patients The volume then moves into investigations of animal models and therapies Drs Hernan and Holmes examine work on antiepileptic treatment strategies in neonatal epilepsy, and Drs Griffin, Krasniak, and Baraban discuss advancement in epilepsy treatment through personalized genetic zebrafish models xi xii Preface Finally, the concluding chapter for the volume is from Drs Prince, Gu, and Parada, describing antiepileptogenic repair of excitatory and inhibitory synaptic connectivity after neocortical trauma Elsa Rossignol, Lionel Carmant, and Jean-Claude Lacaille Departement de neurosciences, Universite de Montreal, Montreal, Canada CHAPTER Multimodal investigation of epileptic networks: The case of insular cortex epilepsy Y Zerouali*,†, J Ghaziri*, D.K Nguyen*,{,1 *Research Centre, Centre hospitalier de l’Universit e de Montr eal, Montreal, QC, Canada † Ecole Polytechnique de Montr eal, Montreal, QC, Canada { CHUM–H^ opital Notre-Dame, Montreal, QC, Canada Corresponding author: Tel.: +1-514-890-8000 ext 25070; Fax: +1-514-338-2694, e-mail address: d.nguyen@umontreal.ca Abstract The insula is a deep cortical structure sharing extensive synaptic connections with a variety of brain regions, including several frontal, temporal, and parietal structures The identification of the insular connectivity network is obviously valuable for understanding a number of cognitive processes, but also for understanding epilepsy since insular seizures involve a number of remote brain regions Ultimately, knowledge of the structure and causal relationships within the epileptic networks associated with insular cortex epilepsy can offer deeper insights into this relatively neglected type of epilepsy enabling the refining of the clinical approach in managing patients affected by it In the present chapter, we first review the multimodal noninvasive tests performed during the presurgical evaluation of epileptic patients with drug refractory focal epilepsy, with particular emphasis on their value for the detection of insular cortex epilepsy Second, we review the emerging multimodal investigation techniques in the field of epilepsy, that aim to (1) enhance the detection of insular cortex epilepsy and (2) unveil the architecture and causal relationships within epileptic networks We summarize the results of these approaches with emphasis on the specific case of insular cortex epilepsy Keywords Epilepsy, Insula, Connectivity, Networks, Multimodal, Causality, Neuroimaging EPILEPSY AS A SYSTEMS DISEASE For most epileptic patients (70%), anticonvulsive drugs adequately control seizures However, among the refractory cases, a significant proportion of patients are eligible for surgical treatment of seizures (Wiebe et al., 2001) The fundamental Progress in Brain Research, Volume 226, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2016.04.004 © 2016 Elsevier B.V All rights reserved CHAPTER Insular cortex epileptic networks question in those cases is to localize the part of the brain that is responsible for patients’ seizures, which constitutes the central thread of this chapter Important advances in the surgical treatment of epilepsy arose from both a better formulation of this question and the development of methodological tools to answer it Indeed, our notion of epilepsy has evolved from a local-based to network-based model, capitalizing on the ability of neuroimaging to study brain function at increasingly high spatial and temporal resolutions Early in the last century, the measurement of brain electrical potentials on the scalp by Berger paved the way for the investigation of the neuroelectric correlates of epileptic seizures In addition to seizures, Berger also reported the existence of sharp electrical transients that are observable on the electroencephalogram (EEG) of epileptic patients in the absence of seizures These “spikes” are usually observed on electrodes that record seizures but this is not always the case This spatial distinction between the generators of seizures and spikes was further elaborated with the advent of intracranial EEG recordings (icEEG) icEEG allows excellent spatial discrimination of the neural generators of epileptic activity, which led Laufs and Rosenow to propose a “zonal” model to explain the pathophysiology of epilepsy (Rosenow, 2001) The “zonal” model recognizes different zones associated with the clinical symptoms (symptomatogenic zone), the interictal spikes (irritative zone), the initiation of seizures (seizure onset zone—SOZ), and the functional deficits associated with the epileptic condition (functional deficit zone) Importantly, they define an “epileptogenic” zone (EZ) that consists of the brain tissue that must be surgically resected for seizures to be cured The spatial location of the EZ is usually estimated using multimodal investigation techniques, as will be described in the next section, but its true location can only be confirmed through positive surgical outcome Although the zonal concept of epilepsy had an important impact on the clinical management of epileptic patients, failure rates for epilepsy surgeries remain relatively important, as high as 30% for temporal lobe—TLE (Jeha et al., 2006; Wiebe et al., 2001) and 50% for frontal lobe—FLE (Jeha et al., 2007; Yun et al., 2006) and parietal lobe—PLE (Binder et al., 2009; Kim et al., 2004a) epilepsy In 2002, Spencer formulated the idea that we should envision generators of interictal and ictal activities as networks of structures rather than single zones (Spencer, 2002) Since the transition from interictal to ictal to postictal brain states occurs at the time scale of synaptic activity, this idea has two corollaries First, it implies that the neural machinery supporting the emergence of epileptogenic networks (ENs) is hardwired into the brain (Richardson, 2012) Thus, epilepsy is a systems disease, the symptoms of which result from aberrant connectivity among a set of anatomical healthy structures (Avanzini and Franceschetti, 2003) Some authors suggest that neural networks are bistable systems that can exhibit both healthy and epileptiform activity for the same set of parameters (Breakspear et al., 2006; Da Silva et al., 2003; Marten et al., 2009) Dynamical transitions between these two states are called bifurcations, and the epileptic condition facilitates such bifurcations The second corollary is that the network assembly is a highly flexible process; for a given set of components, there are a large number of network architectures, all of Investigating the epileptic networks: Clinical practice which may give rise to different epileptiform activities and clinical symptoms This idea has deep implications for clinicians and neuroscientists, since accurate localization of network components is insufficient for fully describing the pathophysiology of epilepsy For such an endeavor, it is necessary to study time-varying network dynamics (Hala´sz, 2010) In order to illustrate the networks concept of epilepsy and the current techniques used in their investigation, we use the unique case of insular cortex epilepsy (ICE) The insula is a cortical structure located deep in the sylvian fissure and is hidden by the frontal, temporal, and parietal opercula Despite early reports on insular epileptiform activity (Guillaume and Mazars, 1949; Penfield and Faulk, 1955; Penfield and Jasper, 1954), insulectomy was not considered an efficient surgical approach (Silfvenius et al., 1964) until the past 15 years Patient series from Isnard et al (2004) and Ryvlin and Kahane (2005) demonstrated that insular ENs include temporal, frontal, and parietal structures and that the sequence of clinical symptoms associated with insular seizures can be explained by their patterns of propagation Throughout this chapter, we will present multimodal investigation techniques used both for localizing the components of ENs and characterizing their architectures, with emphasis on ICE Section presents the investigation techniques that are routinely used in most epilepsy centers for imaging the epileptogenic brain tissues Section presents new experimental investigation techniques that promise enhanced imaging and understanding of ENs INVESTIGATING THE EPILEPTIC NETWORKS: CLINICAL PRACTICE 2.1 PRESURGICAL INVESTIGATION TECHNIQUES 2.1.1 icEEG The gold standard in the localization of the anatomical components of epileptogenic networks consists of direct recordings of neuroelectric activity through electrodes in contact with brain tissue icEEG records local field potentials that are generated by neural populations within a 0.5–3 mm radius from the tip of the electrode (Juergens et al., 1999; Mitzdorf, 1987); thus, achieving the highest spatial resolution among all neuroimaging techniques used in clinic The downside of such high resolution is obviously poor spatial coverage, since only a limited number of electrodes can be used without risking cerebral hemorrhage or neurological deficits (Wong et al., 2009) It is thus possible that the epileptogenic zone is not sampled by icEEG, leading to the wrong selection of surgical target ICE provides an ideal illustration of this issue Insufficient insular coverage in patients with ICE was associated with a significant proportion of failed TLE, FLE, and PLE surgeries Initially, suspicions were raised by a study on patients with TLE with atypical clinical symptoms that were instead associated with insular activity (Aghakhani et al., 2004) Despite successive resections (up to four) of anterior temporal, mesiotemporal, and parietotemporal structures, CHAPTER Insular cortex epileptic networks patients continued having seizures Unfortunately, no electrode sampled the insula in their study although insular hyperperfusion was clearly shown in one patient The potential benefit from icEEG recordings in the insula in TLE was further demonstrated, as about 10% of patients diagnosed with TLE suffered from ICE (Isnard et al., 2004) TLE-like symptoms in those patients were explained by secondary propagation of ictal activity to surrounding temporal structures Similar conclusions were drawn by some studies on PLE and FLE (Roper et al., 1993; Ryvlin et al., 2006) Based on these reports, our group lowered its decision threshold for insular implantations with depth electrodes in patients with nonlesional TLE, FLE, and PLE On a series of 18 patients meeting these criteria, we found that 40% patients who underwent icEEG recordings had seizures originating from the insula In addition, electrical stimulation of the insula proved that insular epileptic discharges replicate semiology of various extrainsular epilepsies (Nguyen et al., 2009) Our findings, along with existing literature on this issue suggest that (1) ICE is probably more prevalent than presently reported; more extensive studies must be conducted to determine its frequency, (2) despite extensive presurgical workups, nonlesional ICE is probably rarely detected, accounting for a significant proportion of failed epilepsy surgeries We further review the different investigation techniques used in presurgical workups and discuss their value for detecting ICE 2.1.2 EEG EEG is probably the oldest and most widely used imaging modality in clinical investigations of brain pathologies, including epilepsy Over the years, epileptologists developed expert skills in reading and interpreting EEG seizures, but also waveforms observed during the interictal state, such as spikes, polyspikes, spikeand-wave complexes, sharp waves, paroxysmal fast activity (Westmoreland, 1998), and high-frequency oscillations (Bragin et al., 1999) Advanced biophysical models and computerized techniques allow unprecedented accuracy in the localization of those waveforms, as most advanced algorithms can theoretically reach a 10 cm2 resolution (Grova et al., 2006), thus enabling “electrical source imaging” (ESI) ESI relies on a biophysical model that relates neural electrical activity, modeled as a finite number of equivalent current dipoles (ECD), to electrical potentials recorded outside the head We distinguish two broad classes of ESI techniques, according to the number ECD used for modeling brain activity Single ECDs assume recorded electrical potentials are generated by a single (or a few) neural point source(s) Although this approach obviously oversimplifies neural generators and its numerical implementation requires strong heuristics (number of dipoles, initialization), it proved valuable in epilepsy when careful attention is paid to its limitations, as validated by simultaneous EEG and icEEG recordings (Boon et al., 2002; Ebersole, 1991; Roth et al., 1997) In general, all studies report usefulness of sECD for epilepsy, with sensitivity and specificity exceeding, respectively, 80% and 60% for the vast majority of studies (see Kaiboriboon et al., 2012, for a review) In turn, distributed source modeling (DSM) models neural sources with a large number of ECDs homogenously distributed in the brain 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Axonal initial segment (AIS), of PNs, 84 Axonal sprouting, 210–215, 211f B Basket cell (BC), 83–84, 85f, 88 Biophysically realistic model, 137–138 Brain-derived neurotrophic factor (BDNF), 97–99, 216–218 Brain somatic mutation, in MTOR, 76 Bumetanide, 185–186 C Cajal–Retzius cells, 134–135 Calcium imaging, 165, 166f Cardiovascular arrhythmias, 199 CASK mutation, 101 Cell death, 128, 130 Channelopathy hypothesis, 36, 39 CHD2, 37–39, 43 Chemical mutagenesis, 201 Chemotaxis of INs, 89–90 Chronic seizures, cortical stroke-induced, 141–142 Circuit reorganization, 127–135 Clemizole, 201 Closed-loop technology, 146 CNVs See Copy number variants (CNVs) Convulsive behavior, zebrafish, 199 Copy number variants (CNVs), 36 in epilepsy, 37–38 Cortical injury, synaptogenesis in models of, 210–215 Cortical INs, 84 Cortical interneuron diversity, 83–85 Cortical malformation, DEPDC5 mutation in, 65–72 Cortical plate (CP), 85f, 89–90 Cortical stroke-induced chronic seizures, 141–142 D Dendritic inhibition, 145 De novo mutation, 36–38, 42–43 DNM1, 43 EEF1A2, 39–42 HCN1, 38–39 SCN1A, 36, 38 Dentate gate theory, 142 Dentate gating, 156, 160–167 Dentate granule cells (DGCs), 155–156 activation, 158–159, 166f GABAergic inhibitory currents in, 169 intrinsic properties of, 156 optogenetic activation of, 165 optogenetic hyperpolarization of, 165 propensity for, 156 shear paucity of, 158–159 sparsely activation, 159–160 Dentate gyrus (DG), 137–138, 155–156 activity in, 156–159 feedback inhibition in, 158 gate breakdown in epilepsy, 167–171 gating function, 161–165, 163–164f mediated transformation, 159–160 position of, 159–160 secondary consequence of, 160–167 DEPDC5 gene, mutational spectrum, 66 DEPDC5 mutation, 67t, 74 in cortical malformations, 65–72 in focal epilepsy syndromes, 64–65 prevalence, 66 DEPDC5 protein, 62, 63f DG See Dentate gyrus (DG) DGCs See Dentate granule cells (DGCs) Diffusion tensor imaging (DTI), 142–144 229 230 Index Dishevelled, Egl-10, and Pleckstrin (DEP) domain, 62 Distributed source modeling (DSM), 4–5, 15 Dlx homeobox transcription factor, 88 Dravet syndrome (DS), 36, 38–39, 45, 94 E EEF1A2, 39–42 EEs See Epileptic encephalopathies (EEs) Electrical source imaging (ESI), Electroencephalogram (EEG), 4–5, 8–9f, 185 connectivity, 15–16, 16f fusion, 10–11 ENs See Epileptogenic networks (ENs) Entorhinal cortex (EC), 157 Epilepsy, 82, 195 See also Posttraumatic epilepsy (PTE) AEDs for genetic, 199–201 CNVs in, 37–38 DG gate breakdown in, 167–171 gene discoveries from 2012 to 2014, 40t massively parallel sequencing in, 38–42 personalized treatments for genetic, 201–203, 202f as systems disease, 1–3 zebrafish as vertebrate model for, 196–198 zonal model, Epileptic encephalopathies (EEs), 36–38 genetic heterogeneity in, 42–43 mutation discovery, 44 phenotypic spectrum extend, 43 precision diagnostics for precision therapy, 44–45 Epileptogenesis, 82, 210, 213–215, 218 Epileptogenic index (EI), 13 Epileptogenic networks (ENs), localization techniques combined EEG and fMRI, 11–13 EEG/MEG connectivity, 15–16, 16f EEG/MEG fusion, 10–11, 11f fMRI connectivity, 16–17 icEEG connectivity, 18–21 neuroimaging brain networks, 14 quantified icEEG, 13 structural connectivity, 17–18 presurgical investigation techniques EEG, 4–5, 8–9f icEEG, 3–4 MEG, MRI, 5–6 PET, 6–7 SPECT, 7, 8–9f Epileptogenic zone (EZ), Equivalent current dipoles (ECD), Excitatory synapse formation, 210–213 Exome sequencing, 38 F Familial focal epilepsy with variable foci (FFEVF), 42 FCD See Focal cortical dysplasia (FCD) fMRI connectivity, 16–17 Focal cortical dysplasia (FCD), 65, 74 Focal epilepsy syndrome, DEPDC5 mutations in, 64–65 Focal seizures, 82 4E-binding protein (4E-BP), 62–64 Fractional anisotropy (FA), 17 G GABA See Gamma-aminobutyric acid (GABA) GABAergic cells, 128–130 GABAergic inhibition, 163f, 168–169 function, abnormalities of, 83 GABAergic interneurons, 83, 158 structural and functional alterations in, 216–218 GABAergic neurons, 130 GABAergic synapse, efficacy of ionotropic, 170 GABAergic synapse formation and maturation, 97–99 Gabapentin (GBP), 213–215 effects of, 213–214 treatment with, 212f, 213–214, 215f Gamma-aminobutyric acid (GABA), 38–39 depolarizing action of, 182–183 excitatory action of, 183 GABAA agonism, 183 immature state of, 183–184 receptor, 162, 169–170, 181 GABAB receptor, 180f, 181 responses, 162–165 synthesis, 100 GAP Activity Toward Rags complex (GATOR1), 62–64 deficiency, animal models of, 75–76 GATOR1/2-mTORC1 pathway, 63f gene mutation, clinical features, 72 mutation to defects in mTORC1 pathway in patient resected brain tissue, 74–75 in vitro functional assays, 74 related epilepsy, singularities of, 72–73 GBP See Gabapentin (GBP) Genetic generalized epilepsy (GGE), 37 Index Genetic heterogeneity in EEs, 42–43 Genetic mutations, 196 Genome-wide association studies (GWAS), 196, 201 Genomic technology application of, 36–37 emergence of, 36 Glial-derived neurotrophic factor (GDNF), 90 Glutamatergic neurons, 83 Granger causality, 15–16 Granule cells, 128, 138–140, 142 Graph theory, 135–137, 136f applications of, 142–146 to control circuits in silico, 137–140, 139f Grid cells, 157 GWAS See Genome-wide association studies (GWAS) H Haploinsufficiency, 186–187 HCN1, 38–39 High-throughput screening, 196–197 Hippocampus, 155–156, 160–162, 164f, 165, 170–171 microcircuits, 129f, 144 sclerosis, 128 Hyperexcitability, 183–184, 187 Hypoxia, 182–183 I ICE See Insular cortex epilepsy (ICE) icEEG See Intracranial EEG recordings (icEEG) Immature brain, enhanced excitability of, 181 Immature neuron, 180–181, 183f blockade of NKCC1 in, 184f GABA in, 182–183 Infantile spasms (IS), 42–43 Inhibitor, isoform-specific NKCC1, 186 Injured cortex, GABAergic interneuron in, 216–218 INs See Interneurons (INs) Insular cortex epilepsy (ICE), 3, 20–21, 22f Interneurons (INs), 83 See also Parvalbumin (PV) INs cell-type specification, 86–87 chemotaxis of, 89–90 cortical, 84 GABAergic, structural and functional alteration, 216–218 MGE-derived, 85f migration of, 90–91 neocortical GABAergic, 83–84 transcription factors regulating migration of, 87–89 Intracranial EEG recordings (icEEG), 2–4 connectivity, 18–21, 21f network dynamics: directionality, 20 network dynamics: ICE, 20–21 network dynamics: synchrony, 19–20 static network properties, 18–19 quantified, 13 In vitro functional assays, 74 Ion channels, postsynaptic voltage-gated, 180f Ischemic neocortex, 213 Isoform-specific NKCC1 inhibitors, 186 K KCNA1 mutations, 95 KCNQ2 mutations, 95–96, 186–187 KCNQ3 mutations, 96, 186–187 KCNT1, 45 Kv channels, neuromodulators of, 96–97 L Landau-Kleffner syndrome, 39 Laser scanning photostimulation (LSPS), 210–214, 211f Lateral ganglionic eminence (LGE), 86 Lennox–Gastaut syndrome (LGS), 42–43 Lhx6 transcription factor, 87 Ligand-gated channels, 180f Locomotion, zebrafish, 199 Lowe syndrome, 198 LSPS See Laser scanning photostimulation (LSPS) M Macrocircuit graph theoretical analysis of, 143f network organization at, 142–146 Magnetic resonance imaging (MRI), 5–6 Magnetoencephalography (MEG), 5, 142–144 connectivity, 15–16, 16f fusion, 10–11 Martinotti cells, SST-positive, 84 Massively parallel sequencing, in epilepsy, 38–42 Maximal dentate activation (MDA), 161–162 Medial temporal lobe epilepsy (MTLE), 98 MEEG, 10–11 MEG See Magnetoencephalography (MEG) Metabotropic glutamate receptors, 181 231 232 Index Microcircuit control, 137–140, 139f of hippocampus, 129f organization and reorganization of, 127–135 Mossy fiber, 137–140 mTOR brain somatic mutation in, 76 protein, 62–64 signaling pathway, 42 mTORC1 signaling pathway, 62–64, 64f Mutagenesis, chemical, 201 Mutation, 44 Mutational spectrum DEPDC5 gene, 66 NPRL2 and NPRL3 gene, 66–72 Myocycte Enhancer Factor 2C (MEF2C), 39 N Na+–K+–Cl– cotransporter (NKCC1), 182–183, 183–184f Neocortex axonal sprouting in partially isolated, 210–213, 211f ischemic, 213 Neocortical GABAergic INs, 83–84 Neonatal period, 179–180 Neonatal seizures, 184–186 bumetanide for, 186 treatment, 186 Neural cell adhesion molecule (NCAM), 98 Neuregulin-1 (NRG1), 89 Neurodevelopmental disability, 185 Neuroimaging brain networks, 14 Neuromodulator, of Kv channels, 96–97 Neuronal circuit, from organization to control of, 135–137 Neuronal excitability voltage-gated potassium channels, 95–97 voltage-gated sodium channels, 94 Neuronal network, 135–137, 140 Neurotransmitter receptor, 180–181 Newly born granule cells, 128 Next-generation sequencing technology, 38–42 NKCC1 See Na+–K+–Cl– cotransporter (NKCC1) Nkx2.1 transcription factor, 87 NMDA receptor, 180f, 181–182 Noninvasive EEG, 142–144 Nonsense-mediated mRNA decay (NMD), 66 NPRL2 and NPRL3 gene mutational spectrum, 66–72 pathogenic mutations in, 67t Nucleokinesis, 91–92 O Optic tectum, 197 Optogenetic closed-loop technology, 146 Optogenetic silencing, 141–142 Optogenetic techniques, 141–142, 165 P Partial cortical isolation model, 220 Partial neocortical isolation, 213–215 Parvalbumin (PV) INs, 84, 85f, 86, 97 cell survival, 93 disorganization of, 99 excitatory and inhibitory innervation of, 101–102 functional specification of, 99 maturation of, 92–93 stimulation of, 104 Patch clamp, 163f Pentylenetetrazole (PTZ), 196 Perinatal asphyxia, 185 Perineuronal nets (PNNs), 92–93 PNNs See Perineuronal nets (PNNs) Polysialic acid (PSA), 98 Positron-emission tomography (PET), 6–7 Postsynaptic voltage-gated ion channels, 180f Posttraumatic epilepsy (PTE), 210 prophylaxis, 220 Potassium channel, voltage-gated, 95–97 Protein mTOR, 62–64 PTE See Posttraumatic epilepsy (PTE) Pyramidal (Pyr) cells, 130, 210–213, 211f Pyramidal neurons (PNs), 83 axonal initial segment of, 84 Q Quantified icEEG, 13 R Rho-GTPAses, 90–91 “Rich gets richer” rule, 137 S Scale-free networks, 138–140 Seizure control, 141–142 Seizure-like activity, 160–161 Seizure onset zone (SOZ), Semaphorins, 90 Sequential imaging approach, 165 Single-nucleotide variants (SNVs), 36 Single-photon emission computerized tomography (SPECT), 7, 8–9f Small-molecule partial agonist, 218, 220 Index Sodium channels, voltage-gated, 94 Somatic mosaic mutation, 44 Somatostatin (SST), 83–84 positive Martinotti cells, 84 SPECT See Single-photon emission computerized tomography (SPECT) Stereo-EEG, 142–144 Stromal-derived factor-1 (SDF1/CXCL12), 91 STXBP1 (syntaxin-binding protein 1) mutations, 101 Sudden unexpected death in epilepsy (SUDEP), 73, 197–199 SUDEP See Sudden unexpected death in epilepsy (SUDEP) Swim behavior, zebrafish, 199 Symptomatogenic zone, Synaptic function, 99–101 Synaptogenesis, 97–99 in models of cortical injury, 210–215 Lhx6, 87 Nkx2.1, 87 regulating migration of INs, 87–89 Trophomyosin receptor kinase B (TrkB), 216–217 functional effects of, 217–218 partial activation of, 219f TSPs See Thrombospondins (TSPs) Tuberous sclerosis complex (TSC), 62–64 Two-photon calcium imaging, 140 T W Temporal lobe epilepsy (TLE) anatomical changes in, 127–135, 129f animal models of, 131t development stages, 137–140 Thrombospondins (TSPs), 213 synaptogenic effects of, 213–214 TLE See Temporal lobe epilepsy (TLE) Tractography, 18 Transcription factor aristaless-related homeobox (Arx), 88 Dlx homeobox, 88 U Urokinase plasminogen activator receptor (uPAR), 89 V Voltage-gated potassium channels, 95–97 Voltage-gated sodium channels, 94 V pyramidal (Pyr) cells, 210–214 Wavelet transform correlation analysis, 144 Whole exome sequencing (WES), 38, 44, 196 Whole genome sequencing, 44, 202f Z Zebrafish larvae cardiac monitoring, 199, 200f electrophysiological recording, 198 modeling genetic epilepsy in, 197–198 tracking locomotion and convulsive behavior, 199 as vertebrate model for epilepsy, 196–197 233 Other volumes in PROGRESS IN BRAIN RESEARCH Volume 167: Stress Hormones and Post Traumatic Stress Disorder: Basic Studies and Clinical Perspectives, by E.R de Kloet, M.S Oitzl and E Vermetten (Eds.) – 2008, ISBN 978-0-444-53140-7 Volume 168: Models of Brain and Mind: Physical, Computational and Psychological Approaches, by R Banerjee and B.K Chakrabarti (Eds.) – 2008, ISBN 978-0-444-53050-9 Volume 169: Essence of Memory, by W.S Sossin, J.-C Lacaille, V.F Castellucci and S Belleville (Eds.) – 2008, ISBN 978-0-444-53164-3 Volume 170: Advances in Vasopressin and Oxytocin – From Genes to Behaviour to Disease, by I.D Neumann and R Landgraf (Eds.) – 2008, ISBN 978-0-444-53201-5 Volume 171: Using Eye Movements as an Experimental Probe of Brain Function—A Symposium in Honor of Jean B€uttner-Ennever, by Christopher Kennard and R John Leigh (Eds.) – 2008, ISBN 978-0-444-53163-6 Volume 172: Serotonin–Dopamine Interaction: Experimental Evidence and Therapeutic Relevance, by Giuseppe Di Giovanni, Vincenzo Di Matteo and Ennio Esposito (Eds.) – 2008, ISBN 978-0-444-53235-0 Volume 173: Glaucoma: An Open Window to Neurodegeneration and Neuroprotection, by Carlo Nucci, Neville N Osborne, Giacinto Bagetta and Luciano Cerulli (Eds.) – 2008, ISBN 978-0-444-53256-5 Volume 174: Mind and Motion: The Bidirectional Link Between Thought and Action, by Markus Raab, Joseph G Johnson and Hauke R Heekeren (Eds.) – 2009, 978-0-444-53356-2 Volume 175: Neurotherapy: Progress in Restorative Neuroscience and Neurology — Proceedings of the 25th International Summer School of Brain Research, held at the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands, August 25–28, 2008, by J Verhaagen, E.M Hol, I Huitinga, J Wijnholds, A.A Bergen, G.J Boer and D.F Swaab (Eds.) –2009, ISBN 978-0-12-374511-8 Volume 176: Attention, by Narayanan Srinivasan (Ed.) – 2009, ISBN 978-0-444-53426-2 Volume 177: Coma Science: Clinical and Ethical Implications, by Steven Laureys, Nicholas D Schiff and Adrian M Owen (Eds.) – 2009, 978-0-444-53432-3 Volume 178: Cultural Neuroscience: Cultural Influences On Brain Function, by Joan Y Chiao (Ed.) – 2009, 978-0-444-53361-6 Volume 179: Genetic models of schizophrenia, by Akira Sawa (Ed.) – 2009, 978-0-444-53430-9 Volume 180: Nanoneuroscience and Nanoneuropharmacology, by Hari Shanker Sharma (Ed.) – 2009, 978-0-444-53431-6 Volume 181: Neuroendocrinology: The Normal Neuroendocrine System, by Luciano Martini, George P Chrousos, Fernand Labrie, Karel Pacak and Donald W Pfaff (Eds.) – 2010, 978-0-444-53617-4 Volume 182: Neuroendocrinology: Pathological Situations and Diseases, by Luciano Martini, George P Chrousos, Fernand Labrie, Karel Pacak and Donald W Pfaff (Eds.) – 2010, 978-0-444-53616-7 Volume 183: Recent Advances in Parkinson’s Disease: Basic Research, by Anders Bj€orklund and M Angela Cenci (Eds.) – 2010, 978-0-444-53614-3 Volume 184: Recent Advances in Parkinson’s Disease: Translational and Clinical Research, by Anders Bj€orklund and M Angela Cenci (Eds.) – 2010, 978-0-444-53750-8 Volume 185: Human Sleep and Cognition Part I: Basic Research, by Gerard A Kerkhof and Hans P.A Van Dongen (Eds.) – 2010, 978-0-444-53702-7 Volume 186: Sex Differences in the Human Brain, their Underpinnings and Implications, by Ivanka Savic (Ed.) – 2010, 978-0-444-53630-3 Volume 187: Breathe, Walk and Chew: The Neural Challenge: Part I, by Jean-Pierre Gossard, Rejean Dubuc and Arlette Kolta (Eds.) – 2010, 978-0-444-53613-6 Volume 188: Breathe, Walk and Chew; The Neural Challenge: Part II, by Jean-Pierre Gossard, Rejean Dubuc and Arlette Kolta (Eds.) – 2011, 978-0-444-53825-3 Volume 189: Gene Expression to Neurobiology and Behaviour: Human Brain Development and Developmental Disorders, by Oliver Braddick, Janette Atkinson and Giorgio M Innocenti (Eds.) – 2011, 978-0-444-53884-0 235 236 Other volumes in PROGRESS IN BRAIN RESEARCH Volume 190: Human Sleep and Cognition Part II: Clinical and Applied Research, by Hans P.A Van Dongen and Gerard A Kerkhof (Eds.) – 2011, 978-0-444-53817-8 Volume 191: Enhancing Performance for Action and perception: Multisensory Integration, Neuroplasticity and Neuroprosthetics: Part I, by Andrea M Green, C Elaine Chapman, John F Kalaska and Franco Lepore (Eds.) – 2011, 978-0-444-53752-2 Volume 192: Enhancing Performance for Action and Perception: Multisensory Integration, Neuroplasticity and Neuroprosthetics: Part II, by Andrea M Green, C Elaine Chapman, John F Kalaska and Franco Lepore (Eds.) – 2011, 978-0-444-53355-5 Volume 193: Slow Brain Oscillations of Sleep, Resting State and Vigilance, by Eus J.W Van Someren, Ysbrand D Van Der Werf, Pieter R Roelfsema, Huibert D Mansvelder and Fernando H Lopes da Silva (Eds.) – 2011, 978-0-444-53839-0 Volume 194: Brain Machine Interfaces: Implications For Science, Clinical Practice And Society, by Jens Schouenborg, Martin Garwicz and Nils Danielsen (Eds.) – 2011, 978-0-444-53815-4 Volume 195: Evolution of the Primate Brain: From Neuron to Behavior, by Michel A Hofman and Dean Falk (Eds.) – 2012, 978-0-444-53860-4 Volume 196: Optogenetics: Tools for Controlling and Monitoring Neuronal Activity, by Thomas Kn€opfel and Edward S Boyden (Eds.) – 2012, 978-0-444-59426-6 Volume 197: Down Syndrome: From Understanding the Neurobiology to Therapy, by Mara Dierssen and Rafael De La Torre (Eds.) – 2012, 978-0-444-54299-1 Volume 198: Orexin/Hypocretin System, by Anantha Shekhar (Ed.) – 2012, 978-0-444-59489-1 Volume 199: The Neurobiology of Circadian Timing, by Andries Kalsbeek, Martha Merrow, Till Roenneberg and Russell G Foster (Eds.) – 2012, 978-0-444-59427-3 Volume 200: Functional Neural Transplantation III: Primary and stem cell therapies for brain repair, Part I, by Stephen B Dunnett and Anders Bj€orklund (Eds.) – 2012, 978-0-444-59575-1 Volume 201: Functional Neural Transplantation III: Primary and stem cell therapies for brain repair, Part II, by Stephen B Dunnett and Anders Bj€orklund (Eds.) – 2012, 978-0-444-59544-7 Volume 202: Decision Making: Neural and Behavioural Approaches, by V.S Chandrasekhar Pammi and Narayanan Srinivasan (Eds.) – 2013, 978-0-444-62604-2 Volume 203: The Fine Arts, Neurology, and Neuroscience: Neuro-Historical Dimensions, by Stanley Finger, Dahlia W Zaidel, Franc¸ois Boller and Julien Bogousslavsky (Eds.) – 2013, 978-0-444-62730-8 Volume 204: The Fine Arts, Neurology, and Neuroscience: New Discoveries and Changing Landscapes, by Stanley Finger, Dahlia W Zaidel, Franc¸ois Boller and Julien Bogousslavsky (Eds.) – 2013, 978-0-444-63287-6 Volume 205: Literature, Neurology, and Neuroscience: Historical and Literary Connections, by Anne Stiles, Stanley Finger and Franc¸ois Boller (Eds.) – 2013, 978-0-444-63273-9 Volume 206: Literature, Neurology, and Neuroscience: Neurological and Psychiatric Disorders, by Stanley Finger, Franc¸ois Boller and Anne Stiles (Eds.) – 2013, 978-0-444-63364-4 Volume 207: Changing Brains: Applying Brain Plasticity to Advance and Recover Human Ability, by Michael M Merzenich, Mor Nahum and Thomas M Van Vleet (Eds.) – 2013, 978-0-444-63327-9 Volume 208: Odor Memory and Perception, by Edi Barkai and Donald A Wilson (Eds.) – 2014, 978-0-444-63350-7 Volume 209: The Central Nervous System Control of Respiration, by Gert Holstege, Caroline M Beers and Hari H Subramanian (Eds.) – 2014, 978-0-444-63274-6 Volume 210: Cerebellar Learning, Narender Ramnani (Ed.) – 2014, 978-0-444-63356-9 Volume 211: Dopamine, by Marco Diana, Gaetano Di Chiara and Pierfranco Spano (Eds.) – 2014, 978-0-444-63425-2 Volume 212: Breathing, Emotion and Evolution, by Gert Holstege, Caroline M Beers and Hari H Subramanian (Eds.) – 2014, 978-0-444-63488-7 Volume 213: Genetics of Epilepsy, by Ortrud K Steinlein (Ed.) – 2014, 978-0-444-63326-2 Volume 214: Brain Extracellular Matrix in Health and Disease, by Asla Pitk€anen, Alexander Dityatev and Bernhard Wehrle-Haller (Eds.) – 2014, 978-0-444-63486-3 Other volumes in PROGRESS IN BRAIN RESEARCH Volume 215: The History of the Gamma Knife, by Jeremy C Ganz (Ed.) – 2014, 978-0-444-63520-4 Volume 216: Music, Neurology, and Neuroscience: Historical Connections and Perspectives, by Franc¸ois Boller, Eckart Altenm€uller, and Stanley Finger (Eds.) – 2015, 978-0-444-63399-6 Volume 217: Music, Neurology, and Neuroscience: Evolution, the Musical Brain, Medical Conditions, and Therapies, by Eckart Altenm€uller, Stanley Finger, and Franc¸ois Boller (Eds.) – 2015, 978-0-444-63551-8 Volume 218: Sensorimotor Rehabilitation: At the Crossroads of Basic and Clinical Sciences, by Numa Dancause, Sylvie Nadeau, and Serge Rossignol (Eds.) – 2015, 978-0-444-63565-5 Volume 219: The Connected Hippocampus, by Shane O’Mara and Marian Tsanov (Eds.) – 2015, 978-0-444-63549-5 Volume 220: New Trends in Basic and Clinical Research of Glaucoma: A Neurodegenerative Disease of the Visual System, by Giacinto Bagetta and Carlo Nucci (Eds.) – 2015, 978-0-444-63566-2 Volume 221: New Trends in Basic and Clinical Research of Glaucoma: A Neurodegenerative Disease of the Visual System, by Giacinto Bagetta and Carlo Nucci (Eds.) – 2015, 978-0-12-804608-1 Volume 222: Computational Neurostimulation, by Sven Bestmann (Ed.) – 2015, 978-0-444-63546-4 Volume 223: Neuroscience for Addiction Medicine: From Prevention to Rehabilitation - Constructs and Drugs, by Hamed Ekhtiari and Martin Paulus (Eds.) – 2016, 978-0-444-63545-7 Volume 224: Neuroscience for Addiction Medicine: From Prevention to Rehabilitation - Methods and Interventions, by Hamed Ekhtiari and Martin P Paulus (Eds.) – 2016, 978-0-444-63716-1 Volume 225: New Horizons in Neurovascular Coupling: A Bridge Between Brain Circulation and Neural Plasticity, by Kazuto Masamoto, Hajime Hirase, and Katsuya Yamada (Eds.) – 2016, 978-0-444-63704-8 237 ... widely used imaging modality in clinical investigations of brain pathologies, including epilepsy Over the years, epileptologists developed expert skills in reading and interpreting EEG seizures,... FDG-PET is negative Since the role of insula has only gained recognition in the last 10 years, early PET studies reporting changes in metabolism in the insula did not include insular intracranial electrodes... number of sources, DSM is increasingly being Investigating the epileptic networks: Clinical practice validated in the clinical management of epileptic patients, benefiting from increased head coverage