This is an open access title available under the terms of a CC BY-NC-ND 4.0 International licence. It is free to read at Oxford Academic and offered as a free PDF download from OUP and selected open access locations.Jasper's Basic Mechanisms of the Epilepsies has served as the definitive reference in the field of basic research in the epilepsies for five decades through four well-regarded editions. Since its inception, the book has been an indispensable must-read and belongs in the hands of every experimental epilepsy investigator, practicing epileptologist, clinical neuroscientist, and student for both clinical and basic science reference, doctoral and board exam preparation.This fifth edition is the most ambitious yet and remains the definitive reference in the field, providing encyclopedic and updated coverage of the current understanding of basic research in the epilepsies, while also mapping new research directions for the next decade, and reviewing how molecular laboratory evidence is now being translated into new therapeutics. In 79 chapters, the book considers the role of interactions between neurons, synapses, and glia in the initiation, spread, and arrest of seizures. It examines mechanisms of excitability, synchronization, seizure susceptibility and, ultimately, their contributions to epileptogenesis. It provides a framework for expanding the monogenic epilepsy genome and understanding the complex heredity responsible for common epilepsies. It explores the molecular and cellular disease mechanisms of ion channelopathies, developmental epilepsy genes, and progressive myoclonic epilepsies. It considers newly emerging mechanisms of epilepsy comorbidities. And, for the first time, it describes current efforts to identify biomarkers of disease progression and translate discoveries of epilepsy disease mechanisms into new therapeutic strategies at the frontier of molecular medicine.

PREFACEDEDICATIONACKNOWLEDGMENTSSECTION 1 - EVOLVING CONCEPTS1. The Paroxysmal Depolarizing Shift (PDS): The First Cellular Marker of Focal EpileptogenesisDavid Prince and Massimo Avoli2. Hippocampal Sclerosis in Temporal Lobe Epilepsy: New Views and ChallengesCarolyn Houser3. Cerebral Cortical Dysplasia or Dysgenesis: Keratan Sulfate Proteoglycan for Fetal Axonal Guidance and Excitatory/Inhibitory Synaptic Targets that Influence EpileptogenesisHarvey Sarnat and Laura Flores-Sarnat4. mTOR in Acquired and Genetic Models of EpilepsyMichael Wong, Angelique Bordey, and Steve C. Danzer5. Epilepsy Genomics: Disease Causing Sequence VariantsAntonio Delgado-EscuetaSECTION 2 - SEIZURES, NETWORKS & SYSTEMSEditor: Massimo Avoli; Associate Editors: Christophe Bernard and Marco de CurtisIntroductionMassimo Avoli, Marco de Curtis, Christophe Bernard, and Ivan Soltesz6. GABAa-Receptor Signaling and Ionic Plasticity in the Generation and Spread of SeizuresKai Kaila, Andrew Trevelyan, Joseph Raimondo, Tommi Ala-Kurikka, Gilles Huberfeld, Massimo Avoli, and Marco de Curtis7. Connexins, Pannexins and EpilepsyLiang Zhang, Georg R. Zoidl, and Peter L. Carlen8. Mechanisms Leading to Initiation, Development and Termination of Focal SeizuresMarco de Curtis, Piotr Suffczynski, Maxime L?vesque, Laura Librizzi,Laura Uva, Paolo Scalmani, Vadym Gnatkovsky, and Massimo Avoli9. Transition to Seizure from Cellular, Network, and Dynamical PerspectivesWei-Chih Chang, Jan Kudlacek, Premysl Jiruska, and John G.R. Jefferys10. Role of the Subiculum in Focal EpilepsyAlesya Evstratova, Bel?n Diaz-Fernandez, Maxime L?vesque, Massimo Avoli, and Gand illes Huberfeld11. Optogenetic Modulation of Focal SeizuresMaxime L?vesque, Massimo Avoli, and Merab Kokaia12. Balancing Seizure Control with Cognitive Side-EffectsSheela Tropani, Gene G Gurkoff, Kiarash Shahlaie, Fady Girgis, Ignacio Saez, Jeffrey Kennedy, and Karen A Moxon13. High Frequency OscillationsLiset Menendes de la Prida and Jean Gotman14. Seizures and SleepBirgit Frauscher and Igor Timofeev15. Cycles in epilepsyMaxime Baud, Vikram Rao, Christophe Bernard, and Philippa Karoly16. Human Single Unit Recordings in EpilepsyEdward Merricks and Catherine Schevon17. Role of Ion Concentration Dynamics in Epileptic SeizuresOscar C Gonz?lez, Igor Timofeev, and Maxim Bazhenov18. A Classification of Seizures Based on DynamicsHiba Sheheitli, Huifang Wang, Jean-Didier Lemarechal, Christophe Bernard, and Viktor K. Jirsa19. Seizures, Networks & Systems - Computational EEG Analysis of Human Epileptogenic NetworksVadim Gnatkovsky and Kaspar Schindler20. Excitation-Inhibition Balance in Absence Seizure IctogenesisMagor L. L?rincz, Vincenzo Crunelli, and Francois David21. Cortical and Thalamic PV+ Interneuron Dysfunction in the Pathogenesis of Absence EpilepsyJochen Meyer and Atul Maheshwari22. Convergence of Thalamic Mechanisms in Genetic EpilepsiesFrances Cho and Jeanne PazSection 3 - EPILEPTOGENESIS: MOLECULAR MECHANISMS & TREATMENTSEditor: Annamaria Vezzani; Associate Editors: Helen Scharfman and David HenshallIntroductionAnnamaria Vezzani and Helen Scharfman23. The Diverse Roles of Mossy Cells in the Normal Brain, Epileptogenesis, and Chronic EpilepsyHelen Scharfman24. Temporal Lobe Epileptogenesis; A Focus on Etiology, Neuron Loss, The Latent Period, and Dentate Granule Cell DisinhibitionRobert Sloviter25. Adult Neurogenesis in Epileptogenesis and ComorbiditiesKyung-Ok Cho and Jenny Hsieh26. A Crucial Role for Astrocytes in Epileptogenesis: Gap Junctions and Glutamate ReceptorsPeter Bedner, Allison R. Peterson, DevinK.Binder, Christian Steinh?user27. Adenosine Kinase: Cytoplasmic and Nuclear IsoformsMadhuvika Murugan and Detlev Boison28. Inflammatory Astrocytic TGF?- Signaling Induced by Blood-Brain Barrier Dysfunction Drives EpileptogenesisLynn T. Yang, Giovanni Anthony, and Daniela Kaufer29. Pericytes and Microglia: Neurovascular and Immune Regulatory Cells in Seizure DisordersNicola Marchi and Amy Brewster30. Neuroinflammation in Epilepsy: Cellular and Molecular MechanismsRay Dingledine, Nicholas Varvel, Teresa Ravizza, and Annamaria Vezzani31. Role of Reactive Oxygen Species in EpilepsyAshwini Sri Hari, Matthew C. Walker, and Manisha Patel32. BDNF/TrkB Signaling and EpileptogenesisStephen Harward, Yang Huang, and James McNamara33. Clinical Features and Molecular Mechanisms Underlying Autoantibody-Mediated SeizuresAlexander Mathy and Sarosh Irani34. Transcriptomic Alterations in Epileptogenesis: Transcription Factors in the SpotlightGary Brennan and Karen van Loo35. EpigeneticsKatja Kobow and Nadia KhanSECTION 4 - BIOMARKERS OF EPILEPTOGENESISEditor: Annamaria Vezzani; Associate Editors: Helen Scharfman and David HenshallIntroductionAnnamaria Vezzani and David Henshall36. EEG Biomarkers of EpileptogenesisLyna Kamintsky, Dan Z Milikovsky, and Alon Friedman37. Blood Biomarkers: Noncoding RNAs and ProteinsDavid Henshall and Michele Simonato38. Behavioural Biomarkers of Epileptogenesis and Epilepsy SeverityIdrish Ali, Pablo Casillas-Espinosa, Nigel Jones, and Terence O'Brien39. Genetic and Imaging Biomarkers of EpileptogenesisMatthias Koepp, Simona Balestrini, Stefanie Dedurwaerdere, and William Theodore40. Machine-Learning Approach to Discover Novel Biomarkers for Post-Traumatic EpilepsyRobert Ciszek, Eppu Manninen, Olli Gr?hn, Jussi Tohka, and Asla Pitk?nenSECTION 5 - GENES AND NETWORK DEVELOPMENTEditors: Antonio Delgado Escueta and Jeffrey Noebels; Associate Editor: Elsa RossignolIntroductionJeffrey Noebels41. Human Epilepsy Gene Discovery: The Next DecadeEmily Bonkowski and Heather Mefford42. Functional Exploration of Epilepsy Genes in Patint-Derived CellsMaria 'Carmen' Varela, Ranmal Samarasinghe, and Jack Parent43. Brain mosaicism in Epileptogenic Cortical MalformationsTh?o Ribierre and St?phanie Baulac44. Sodium Channelopathies in Human and Animal Models of Epilepsy and Neurodevelopmental DisordersKazuhiro Yamakawa, Miriam Meisler, and Lori Isom45. Potassium Channels in Genetic Epilepsy: a Functional PerspectiveMatthew Weston and Anastasios Tzingounis46. High Voltage Activated Calcium Channels in Epilepsy: Lessons from Humans and RodentsElsa Rossignol47. Transcription Factors Regulating Interneuron DevelopmentEmily Ling-Lin Pai, Daniel Vogt, Jia Sheng Hu, and John Rubenstein48. GABAA Receptors, Seizures and EpilepsyRichard Olsen, Martin Wallner, and Michael A. Rogawski49. Gene genome interactions - Understanding complex molecular traits in epilepsyKatja Kobow and John MahoneySECTION - 6 PROGRESSIVE MYOCLONUS EPILEPSIESEditor: Antonio Delgado-Escueta; Associate Editor: Berge MinassianIntroductionA.V. Delgado-Escueta, Berge Minassian, Jose M Seratossa50. The Neuronal Ceroid LipofuscinosesSara Mole51. Progressive Myoclonus Epilepsy: Unverricht-Lundborg DiseaseSaara Tegelberg, Tarja Joensuu, and Anna-Elina Lehesjoki52. Strategies on Gene Therapy in Progressive Myoclonus EpilepsiesSaima Kayani, Emrah Gumusgoz, Berge Minassian, and Alison Dolce53. Therapeutic Window for the Treatment of Lafora DiseaseOlga Varea, Joan Guinovart, and Jordi Duran54. Progressive Myoclonus Epilepsy of Lafora- Treatment with MetforminJose M. Seratossa, Daniel F. Burgos, Luis Zafra-Puerta, Nerea Iglesias-Cabeza, Pascual Sanz, and Marina P. S?nchez55. Treating Lafora Disease with an Antibody-Enzyme FusionMatthew Gentry, Kia H. Markussen, Ramon Sun, and Craig W. Vander Kooi56. Antisense Oligonucleotide Therapy for Progressive Myoclonus EpilepsiesSilvia Nitschke and Berge MinassianSECTION 7 - COMORBIDITIES OF EPILEPTIC NETWORKSEditor: Jeffrey Noebels; Associate Editor: Peyman GolshaniIntroductionJeffrey Noebels57. Dissecting Epileptic and Cognitive Network Dysfunction in EpilepsyPierre-Pascal Lenck-Santini and Greg Holmes58. Attention Deficit Disorders and EpilepsyAtul Maheshwari59. What Rodent Models Teach Us About the Association of Autism and EpilepsyPeyman Golshani60. Artificial Intelligence-Guided Behavioral Phenotyping in EpilepsyTilo Gschwind and Ivan Soltesz61. Mechanisms of Depression in the Epileptic BrainNigel Jones and Jamie Maguire62. Heterogeneous Mechanisms of Spreading Depolarization and SeizuresIsamu Aiba63. Genetic and Cellular Mechanisms Underlying SUDEP RiskJeffrey NoebelsSECTION 8- EPILEPSY THERAPEUTICSEditor: Michael Rogawski; Associate Editors: Wolfgang L?scher & Steve WhiteIntroductionMichael Rogawski64. New Models for Assessment of Antiseizure ActivityCameron Metcalf, Peter West, Sharon Edwards, and Karen Wilcox65. Disease Biology Factors Accounting for Epilepsy Severity: An Updated Conceptual Framework for New Drug DiscoveryStefanie Dedeurwaerdere, Vincenzo Marra, and Michael R Johnson66. Animal Models of Pharmacoresistant EpilepsyMichelle Guignet and H. Steve White67. Drug Combinations for AntiepileptogenesisWolfgang L?scher68. Prophylaxis of Epileptogenesis in Injury and Genetic Epilepsy ModelsDavid Prince and Feng Gu69. Management of Febrile Status Epilepticus: Past, Present and FutureMegan M. Garcia-Curran and Tallie Z. Baram70. Excitatory Transmission in Status EpilepticusSuchitra Joshi and Jaideep Kapur71. Ionic Mechanisms of Ictogenic Disinhibition: All GABA Signaling is LocalKevin Staley72. Epileptogenic Channelopathies Guide Design of NBI-921352, a Highly Isoform-Selective Inhibitor of NaV1.6J.P. Johnson, Jr, Alison J Cutts, James R. Empfield, and Charles J. Cohen73. Purinergic Signaling in EpilepsyTobias Engel and Nicholas Dale74. Anti-Inflammatory Strategies for Disease Modification: Focus on Therapies Close to Clinical TranslationAnnamaria Vezzani, Silvia Balosso, Nicholas H. Varvel, and Ray Dingledine75. Targeted Augmentation of Nuclear Gene Output (TANGO)Lori Isom and Kelly G. Knupp76. Gene Therapy for EpilepsyKimberly Goodspeed, Dallas Armstrong, Andrea Boitnott, Alison Dolce, Qinglan Ling, and Steve Gray77. Gene Therapy for Refractory EpilepsyDimitri Kullmann78. Cell Therapy for Treatment of EpilepsySonja Br?er and Daniel Vogt79. Mechanisms of Ketogenic Diet ActionRobin Williams, Detlev Boison, Susan Masino, and Jong Rho