Abstract

This resource, considered the 'bible' of basic epilepsy research, offers encyclopedic coverage and in depth discussions of leading research hypotheses and strategic approaches. Indispensable for students and all research scientists in the field of epilepsy research, and now of practical importance to the clinic, it also maps out new research directions for the next decade.

Contents

• Copyright Page
• Dedication
• Preface
• Jasper’s Basic Mechanisms of the Epilepsies Workshops Yosemite National Park, March 4–8, 2019
• Acknowledgments
• Contributors
• Section 1. Evolving Concepts
  • 1. The Paroxysmal Depolarizing Shift: The First Cellular Marker of Focal Epileptogenesis
    David A. Prince and Massimo Avoli.
    • Abstract
    • Introduction
    • Neuronal Networks, Synaptic and Intrinsic Membrane Currents, and PDS Generation
    • Intrinsic Neuronal Properties and PDS Generation
    • Role of Dendritic Ca²⁺ Spikes in PDS Generation
    • Dendritic Abnormalities in Models of Epilepsy
    • Concluding Remarks
    • Acknowledgments
    • Disclosure Statement
    • References
  • 2. Hippocampal Sclerosis in Temporal Lobe Epilepsy: New Views and Challenges
    Carolyn R. Houser.
    • Abstract
    • Introduction
    • What Are the Patterns of Cell Loss in Hippocampal Sclerosis?
    • What Neurons Remain and How Are They Altered?
    • What Is the Circuitry among Remaining Neurons?
    • Future Directions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 3. Cerebral Cortical Dysplasia or Dysgenesis: Keratan Sulfate Proteoglycan for Fetal Axonal Guidance and Excitatory/Inhibitory Synaptic Targets That Influence Epileptogenesis
    Harvey B. Sarnat and Laura Flores-Sarnat.
    • Abstract
    • Introduction
    • Developmental Principles of Neuroembryology and Cerebral Dysgenesis
    • Keratan Sulfate in Fetal Axonal Guidance
    • Keratan Sulfate at Glutamatergic and GABAergic Synaptic Membranes
    • Examples of Epileptogenic Dysplasias Influenced by Keratan Sulfate
    • Examples of Less Epileptogenic or Non-Epileptogenic Disorders Influenced by Keratan Sulfate
    • Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 4. mTOR in Acquired and Genetic Models of Epilepsy
    Michael Wong, Angelique Bordey, and Steve C. Danzer.
    • Abstract
    • The mTOR Signaling Pathway
    • Clinical Disorders Caused by mTOR Pathway Mutations
    • Genetic Models of mTORopathies
    • Molecular Mechanisms of Epileptogenesis due to mTOR Hyperactivation
    • Morphological and Pathological Effects of mTOR Hyperactivation on Cell Structure
    • Genetic Effects: Not All mTORopathy Genes Are Equal
    • mTOR Hyperactivation in Acquired Epilepsy
    • Challenges and Opportunities
    • Acknowledgments
    • Disclosure Statement
    • References
  • 5. Epilepsy Genomics: Disease-Causing Sequence Variants
    Antonio V. Delgado-Escueta.
    • Abstract
    • Introduction
    • History of Curating the Epilepsy Genome: The First Ten Years of Epilepsy Variants
    • Benefits of Curating the Epilepsy Genome
    • Epilepsy Genomics: At Last a Road to Halting and Reversing Disease Progression and Possible Cures
    • Remaining Challenges and Trends in the Next Ten Years
    • References
• Section 2. Seizures, Networks, and Systems
  Massimo Avoli, Marco de Curtis, Christophe Bernard, and Ivan Soltesz.
  • 6. GABA_A-Receptor Signaling and Ionic Plasticity in the Generation and Spread of Seizures
    Kai Kaila, Andrew Trevelyan, Joseph Raimondo, Tommi Ala-Kurikka, Gilles Huberfeld, Massimo Avoli, and Marco de Curtis.
    • Abstract
    • Introduction
    • Network Patterns of Focal Seizures
    • Activity-Dependent Ionic Mechanisms Underlying Fast Transformation from Inhibitory to Excitatory GABA_AR Signaling
    • Ionic Avalanches in the Generation and Spread of Seizures
    • Chronic Epilepsy and Long-Term Ionic Plasticity
    • Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 7. Connexins, Pannexins, and Epilepsy
    Liang Zhang, Georg R. Zoidl, and Peter L. Carlen.
    • Abstract
    • Introduction
    • Fundamental Biology of Gap Junctions, Connexins, and Pannexins
    • Gap Junctions and Epilepsy
    • Pannexins and Seizures
    • Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 8. Mechanisms Leading to Initiation, Development, and Termination of Focal Seizures
    Marco de Curtis, Piotr Suffczynski, Maxime Lévesque, Laura Librizzi, Laura Uva, Paolo Scalmani, Vadym Gnatkovsky, and Massimo Avoli.
    • Abstract
    • Introduction
    • Focal Seizure Patterns in Humans
    • Focal Seizure Patterns in Animal Models
    • Focal Seizure Onset
    • Progression of a Focal Seizure Discharge
    • Focal Seizure Termination
    • The Relationship between Focal Seizure Termination and Postictal Suppression
    • Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 9. Transition to Seizure from Cellular, Network, and Dynamical Perspectives
    Wei-Chih Chang, Jan Kudlacek, Premysl Jiruska, and John G. R. Jefferys.
    • Abstract
    • Introduction
    • Seizure Initiation
    • Transition to the Seizure and Preictal State
    • The Phenomenon of Critical Slowing and Loss of Resilience
    • Experimental and Empirical Evidence for a Critical Slowing and Loss of Stability in the Epileptic Brain
    • Empirical Evidence for a Preictal Critical Slowing and Loss of Stability in Humans
    • Proictal States, Seizure Probability Fluctuation, and Markers of Resilience
    • Conclusions and Future Research
    • Acknowledgments
    • Disclosure Statement
    • References
  • 10. Role of the Subiculum in Focal Epilepsy
    Alesya Evstratova, Belén Diaz-Fernandez, Maxime Lévesque, Massimo Avoli, and Gilles Huberfeld.
    • Abstract
    • Introduction
    • Subiculum: Anatomy, Local Networks, and Cellular Properties
    • Subiculum Physiology: More Than a Hippocampal Output
    • Role of the Subiculum in Rodent Models of Epilepsy
    • Role of the Subiculum in Human Focal Epilepsy
    • Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 11. Optogenetic Modulation of Focal Seizures
    Maxime Lévesque, Massimo Avoli, and Merab Kokaia.
    • Abstract
    • Introduction
    • Optogenetic Stimulation in In Vitro Models of Epileptiform Synchronization
    • Optogenetic Stimulation in In Vivo Models of Mesial Temporal Lobe Epilepsy
    • Limitations and Clinical Translation of Optogenetic Procedures
    • Concluding Remarks
    • Acknowledgments
    • Disclosure Statement
    • References
  • 12. Balancing Seizure Control with Cognitive Side Effects Using Changes in Theta
    Sheela Toprani, Gene G. Gurkoff, Kiarash Shahlaie, Fady Girgis, Ignacio Saez, Jeffrey Kennedy, and Karen A. Moxon.
    • Abstract
    • Introduction
    • Network Approach to Epileptic Seizures
    • Pathological Theta and Relationship to Interneurons Preictally
    • Pathological Theta-Related Decrease in Neuronal Activity Interictally
    • Pathological Theta and Reduced Cognitive Performance
    • Stimulation of Theta Reduces Ictogenesis and Attenuates Cognitive Dysfunction
    • Impact of an Inclusive Framework on Treatment
    • References
  • 13. High-Frequency Oscillations
    Liset Menendez de la Prida and Jean Gotman.
    • Abstract
    • Definitions
    • Recording Methods
    • Separating Physiological from Pathological HFOs
    • Basic Mechanisms of Generation
    • Are There Different Mechanisms in Neocortex?
    • Visual Analysis and Automatic Detection in Clinical Settings
    • Relationships to the Epileptogenic Zone
    • Fast Ripples and the Underlying Anatomopathological Entities
    • Biomarker of Epilepsy
    • Conclusion
    • References
  • 14. Seizures and Sleep
    Birgit Frauscher and Igor Timofeev.
    • Abstract
    • Neuronal Activity during Sleep Oscillations and Epileptic Activity
    • Bidirectional Interactions between Epileptic Activity and Sleep
    • Effects of Sleep Homeostasis and Circadian, Multidien, and Circannual Rhythms of Epileptic Activity
    • Effects of Sleep-Related Epileptic Activity on Sleep Structure and Function
    • SUDEP, Seizures, and Sleep
    • Future Directions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 15. Cycles in Epilepsy
    Maxime O. Baud, Vikram R. Rao, Christophe Bernard, and Philippa J. Karoly.
    • Abstract
    • Introduction
    • Historical Perspective
    • Methodological Advances
    • Sleep-Wake and Circadian Seizure Cycles
    • Multidien Seizure Cycles
    • Circannual Seizure Cycles
    • Impact and Future Challenges
    • Disclosure Statement
    • References
  • 16. Human Single-Neuron Recordings in Epilepsy
    Edward M. Merricks and Catherine A. Schevon.
    • Abstract
    • Introduction
    • Devices for Recording Single Neurons in Humans
    • Recording Methodology and Technical Considerations
    • Single- and Multi-Unit Discrimination and Analyses
    • Insights into Ictal Dynamics from Human Single-Neuron Recordings
    • Human Single-Neuron Activity in the Interictal Period
    • Single-Neuron Neurocognitive Studies in Epilepsy Patients
    • Future Considerations
    • Disclosure Statement
    • References
  • 17. Role of Ion Concentration Dynamics in Epileptic Seizures
    Oscar C. González, Igor Timofeev, and Maxim Bazhenov.
    • Abstract
    • Introduction
    • Potassium Ions and the K⁺ Accumulation Hypothesis
    • Sodium Ions and the Na⁺/K⁺ Pump
    • Chloride
    • Calcium and Magnesium
    • Conclusion
    • Acknowledgments
    • References
  • 18. A Classification of Seizures Based on Dynamics
    Hiba Sheheitli, Huifang Wang, Jean-Didier Lemarechal, Christophe Bernard, and Viktor K. Jirsa.
    • Abstract
    • Introduction
    • A Taxonomy of Seizure Dynamics
    • Application to Clinical Data
    • Implications for the Clinic
    • Conclusion
    • References
  • 19. Computational EEG Analysis of Human Epileptogenic Networks
    Vadym Gnatkovsky and Kaspar Schindler.
    • Abstract
    • Introduction
    • Scalp EEG
    • Intracranial Stereo-EEG
    • Epileptogenicity Index
    • Statistical Parametric Mapping of Epileptogenicity Index
    • Quantified Frequency Analysis Index
    • Nonlinear Structure Index
    • High-Frequency Oscillations
    • Ultra-Long-Term EEG
    • The Next Ten Years
    • Disclosure Statement
    • References
  • 20. Excitation-Inhibition Balance in Absence Seizure Ictogenesis
    Magor L. Lőrincz, Vincenzo Crunelli, and Francois David.
    • Abstract
    • Intrinsic Mechanisms
    • Network/Synaptic Mechanisms
    • SWD Frequency in Animal Models and Humans
    • Conclusions
    • Acknowledgments
    • Disclaimer Statement
    • References
  • 21. Cortical and Thalamic PV+ Interneuron Dysfunction in the Pathogenesis of Absence Epilepsy
    Jochen Meyer and Atul Maheshwari.
    • Abstract
    • The Corticothalamic Circuit Involved with Absence Epilepsy
    • Genetic and Molecular Insights into Cell-Type-Specific Contributions to Absence Epilepsy
    • Insights into Network Mechanisms from Recent In Vivo Imaging and Minimally Invasive Manipulation Studies
    • New Directions and Treatment Considerations
    • Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 22. Convergence of Thalamic Mechanisms in Genetic Epilepsies
    Frances S. Cho and Jeanne T. Paz.
    • Abstract
    • Introduction
    • Thalamic Organization and Rhythmogenesis
    • Structural Elements of Thalamic and Thalamocortical Circuits: From Gross Anatomy to Cell Types
    • Thalamic Firing
    • Calcium Channels and Thalamic Firing
    • Rhythmogenesis in the Thalamus: Strengths and Weaknesses
    • The Thalamus in Absence Epilepsy and Beyond
    • The Emerging Role of the Thalamus in Acquired Epilepsies
    • Conclusions
    • Acknowledgments
    • References
• Section 3. Epileptogenesis: Molecular Mechanism and Treatments
  Annamaria Vezzani and Helen E. Scharfman.
  • 23. The Diverse Roles of Mossy Cells in the Normal Brain, Epileptogenesis, and Chronic Epilepsy
    Helen E. Scharfman.
    • Abstract
    • Introduction: Defining Mossy Cells
    • Functional Role of MCs in the Normal DG
    • MCs in Epileptogenesis and Epilepsy
    • Caveats and Open Questions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 24. Temporal Lobe Epileptogenesis: A Focus on Etiology, Neuron Loss, the Latent Period, and Dentate Granule Cell Disinhibition
    Robert S. Sloviter.
    • Abstract
    • Introduction
    • Three Steps to Refractory Temporal Lobe Epilepsy When Prolonged Febrile Seizures Are an Antecedent Factor
    • Excitotoxicity, Neuron Loss, Disinhibition, and Temporal Lobe Epileptogenesis
    • The Latent Period; When after Injury Do Self-Generated Epileptic Seizures Begin?
    • Is Dentate Gyrus Disinhibition a Directly Epileptogenic Mechanism?
    • A Unifying Theory of Inherited and Acquired TLE Epileptogenesis
    • Unaddressed and Unanswered Questions
    • Synopsis
    • Acknowledgments
    • Disclosure Statement
    • References
  • 25. Adult Neurogenesis in Epileptogenesis and Comorbidities
    Kyung-Ok Cho and Jenny Hsieh.
    • Abstract
    • Concept of Epileptogenesis
    • Morphological Changes of Adult-Born Granule Cells in Epilepsy
    • Molecular Regulators of Aberrant Neurogenesis in Epilepsy
    • Glial Control of Aberrant Neurogenesis in Epilepsy
    • Functional Roles of Adult Hippocampal Neurogenesis in Acute and Chronic Phase of Epilepsy
    • Role of Aberrant Neurogenesis in Epilepsy-Associated Comorbidities
    • Conclusions and Future Perspectives
    • Acknowledgments
    • Disclosure Statement
    • References
  • 26. A Crucial Role for Astrocytes in Epileptogenesis: Gap Junctions and Glutamate Receptors
    Peter Bedner, Allison R. Peterson, Devin K. Binder, and Christian Steinhäuser.
    • Abstract
    • Introduction
    • Gap Junction Channels
    • Glutamate Receptors
    • Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 27. Adenosine Kinase: Cytoplasmic and Nuclear Isoforms
    Madhuvika Murugan and Detlev Boison.
    • Abstract
    • Introduction
    • The Biochemistry of Adenosine: Role in Epilepsy
    • Adenosine Kinase Hypothesis of Epileptogenesis
    • Targeting ADK for Epilepsy Treatment
    • Conclusions and Therapeutic Perspective
    • Acknowledgments
    • Disclosure Statement
    • References
  • 28. Inflammatory Astrocytic TGFβ Signaling Induced by Blood–Brain Barrier Dysfunction Drives Epileptogenesis
    Lynn T. Yang, Giovanni Anthony, and Daniela Kaufer.
    • Abstract
    • Introduction
    • The Blood–Brain Barrier
    • BBBD in Epileptogenesis
    • Translational Impact—Therapeutic Approaches to BBB Dysfunction in Epilepsy
    • Conclusions
    • Acknowledgments
    • References
  • 29. Pericytes and Microglia: Neurovascular and Immune Regulatory Cells in Seizure Disorders
    Nicola Marchi and Amy L. Brewster.
    • Abstract
    • Introduction: Neuro-Glio-Vascular Regulatory Cells in Seizure Networks
    • What Is a Pericyte?
    • Perivascular Inflammatory Cell Reactivity during Seizures: Focus on Pericytes
    • What Are Microglial Cells?
    • Microglia Surveillance and Neuronal Interactions
    • Microglial Pro- and Anti-inflammatory Molecular Equilibriums in Experimental Epilepsy
    • Microglia-Pericytes Perivascular Assembly and Reactivity during Seizures: Experimental and Clinical Evidence
    • Microglial Profiles in Human Drug-Resistant Epilepsies
    • Pharmacological Entry Points: Focus on Pericytes and Microglia
    • Conclusion: Refining Timing and Targets for Pharmacological Interventions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 30. Neuroinflammation in Epilepsy: Cellular and Molecular Mechanisms
    Ray Dingledine, Nicholas H. Varvel, Teresa Ravizza, and Annamaria Vezzani.
    • Abstract
    • Introduction
    • Cytokines
    • Inflammation-Induced Channelopathies: Impact on Neuronal Excitability and Comorbidities
    • COX-2 Signaling Pathways
    • Chemokines
    • Complement Pathway
    • Variants in Immune-Related Genes
    • Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 31. Role of Reactive Oxygen Species in Epilepsy
    Ashwini Sri Hari, Matthew C. Walker, and Manisha Patel.
    • Abstract
    • Introduction
    • Neuron-Glial Interactions and Their Role in Metabolic Dysfunction Associated with Seizures
    • Role of Oxidative and Nitrosative Stress in Epilepsy
    • Redox Homeostasis
    • Sources of Reactive Oxygen Species Production
    • Redox-Mediated Cellular Pathway Disruption in Epilepsy
    • Biomarkers
    • Therapeutic Strategies
    • Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 32. BDNF/TrkB Signaling and Epileptogenesis
    Stephen C. Harward, Yang Zhong Huang, and James O. McNamara.
    • Abstract
    • Introduction
    • BDNF and TrkB Biology
    • BDNF/TrkB Signaling: Epileptogenesis Caused by Trauma
    • BDNF/TrkB Signaling: Development of Epilepsy Caused by Hypoxic/Ischemic Insults
    • BDNF/TrkB Signaling: Development of Epilepsy Caused by Seizures
    • BDNF/TrkB Signaling: A Role in Neuronal Survival
    • Summary and Perspective
    • References
  • 33. Clinical Features and Molecular Mechanisms Underlying Autoantibody-Mediated Seizures
    Alexandre Mathy and Sarosh R. Irani.
    • Abstract
    • Introduction
    • Clinical Features of Antibody-Mediated CNS Disorders
    • Immunopathogenesis
    • Neuropathogenesis
    • Conclusions
    • Disclosure Statement
    • Acknowledgments
    • References
  • 34. Transcriptomic Alterations in Epileptogenesis: Transcription Factors in the Spotlight
    Gary P. Brennan and Karen M. J. van Loo.
    • Abstract
    • Introduction
    • Transcriptional Control by FOS and JUN
    • Transcriptional Control by Early Growth Response Genes
    • Transcriptional Control by Serum Response Factor
    • Transcriptional Control by the CREB Signaling Pathway
    • Transcriptional Control Mechanisms by SP1
    • Inflammation-Associated Transcriptional Regulation by NF-kB
    • The JAK/STAT Signaling Cascade
    • Zn²⁺-Induced Transcriptional Control
    • Circadian Clock-Controlled Transcription
    • NRF2-Mediated Control of Antioxidant Defenses
    • Transcriptional Repression by RE1-Silencing Transcription Factor
    • Genetic Variants and Transcriptional Control Mechanisms
    • Differential Transcriptional Regulation by Alternative Promoters
    • Summary and Future Course
    • Acknowledgments
    • References
  • 35. Epigenetics
    Katja Kobow and Nadia Khan.
    • Abstract
    • Introduction
    • Basic Concepts
    • Key Epigenetic Mechanisms
    • On the Epigenetic Origin of Epilepsy
    • Epigenetic Biomarkers in Epilepsy
    • Outlook
    • References
• Section 4. Biomarkers of Epileptogenesis
  Annamaria Vezzani and David Henshall.
  • 36. EEG Biomarkers of Epileptogenesis
    Lyna Kamintsky, Dan Z. Milikovsky, and Alon Friedman.
    • Abstract
    • The Electroencephalogram
    • EEG as a Biomarker for Epileptogenesis
    • EEG Signatures of Epileptogenesis
    • Future Challenges and Potential Mitigation Strategies
    • Future Opportunities
    • Conclusions
    • References
  • 37. Blood Biomarkers: Noncoding RNAs and Proteins
    David C. Henshall and Michele Simonato.
    • Abstract
    • Introduction
    • Why Should Circulating Biofluids Contain Molecular Biomarkers of Epilepsy?
    • Other Criteria That Must Be Met for Circulating Molecular Biomarkers
    • What Type of Molecules Should We Be Looking for?
    • How Would a Molecular Biomarker Be Used?
    • miRNAs as Epilepsy Biomarkers
    • Current Gaps—What We Know We Don’t Know
    • Summary and Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 38. Behavioral Biomarkers of Epileptogenesis and Epilepsy Severity
    Idrish Ali, Pablo M. Casillas-Espinosa, Nigel C. Jones, and Terence J. O’Brien.
    • Abstract
    • Introduction
    • Neurobehavioral Comorbidities of Epilepsy: Bidirectional Relationship
    • Behavioral Comorbidities as Biomarkers of Epileptogenesis
    • Behavioral Comorbidities as Biomarkers of Epilepsy Severity
    • Conclusions and Future Directions
    • References
  • 39. Genetic and Imaging Biomarkers of Epileptogenesis
    Matthias J. Koepp, Simona Balestrini, Stefanie Dedeurwaerdere, and William H. Theodore.
    • Abstract
    • Introduction
    • Genetic Biomarkers
    • Imaging Biomarkers
    • Conclusions
    • References
  • 40. Machine-Learning Approach to Discover Novel Biomarkers for Posttraumatic Epilepsy
    Robert Ciszek, Eppu Manninen, Olli Gröhn, Jussi Tohka, and Asla Pitkänen.
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Disclosure Statement
    • References
• Section 5. Genes and Network Development
  Jeffrey L. Noebels.
  • 41. Human Epilepsy Gene Discovery: The Next Decade
    Emily S. Bonkowski and Heather C. Mefford.
    • Abstract
    • Genetic Contributions to Epilepsy: Current Knowledge
    • What’s Next?
    • Summary
    • References
  • 42. Functional Exploration of Epilepsy Genes in Patient-Derived Cells
    Maria C. Varela, Ranmal Samarasinghe, and Jack M. Parent.
    • Abstract
    • Introduction
    • Generating iPSCs
    • Gene Editing of iPSCs
    • Methods of 2D Neuronal Differentiation
    • Physiological Assays for hPSC-Derived Neurons
    • Genetic Epilepsy Modeling Using 2D hPSC Cultures
    • Brain Organoid Models
    • Modeling Genetic Epilepsies and Their Effects on Cortical Network Function With Brain Organoids
    • Challenges and Future Directions
    • Conclusions
    • References
  • 43. Brain Mosaicism in Epileptogenic Cortical Malformations
    Théo Ribierre and Stéphanie Baulac.
    • Abstract
    • Introduction
    • Modeling of Brain Somatic Mutations in Rodents
    • Cellular and Circuit Features Underlying Focal Cortical Dysplasia
    • Disease Modeling Using Human Stem Cell Models
    • Precision Medicine and Perspectives
    • Disclosure Statement
    • Acknowledgments
    • References
  • 44. Sodium Channelopathies in Human and Animal Models of Epilepsy and Neurodevelopmental Disorders
    Kazuhiro Yamakawa, Miriam H. Meisler, and Lori L. Isom.
    • Abstract
    • Introduction
    • SCN1A
    • SCN2A
    • SCN8A
    • SCN1B
    • Concluding Remarks
    • Disclosure Statement
    • References
  • 45. Potassium Channels in Genetic Epilepsy: A Functional Perspective
    Matthew C. Weston and Anastasios V. Tzingounis.
    • Abstract
    • Introduction
    • Brief Summary of Potassium Channel Classification
    • Types of Potassium Currents in Neurons
    • New Concepts, Gaps in Our Knowledge, and Novel Approaches
    • Conclusion
    • Acknowledgments
    • Disclosure Statement
    • References
  • 46. High-Voltage-Activated Calcium Channels in Epilepsy: Lessons from Humans and Rodents
    Elsa Rossignol.
    • Abstract
    • Introduction
    • Voltage-Gated Calcium Channels: An Overview
    • L-Type VGCCs in Epilepsy
    • P/Q-Type Ca_V2.1 VGCC and Epilepsy
    • R-Type Ca_V2.3 Channels: CACNA1E-Associated Epilepsy
    • Conclusions
    • Acknowledgments
    • References
  • 47. Transcriptional Regulation of Cortical Interneuron Development
    Emily Ling-Lin Pai, Daniel Vogt, Jia Sheng Hu, and John L. Rubenstein.
    • Abstract
    • Introduction
    • Subpallial Progenitor Domain Subdivisions
    • Regional Specification of IN-Generating Progenitor Zones
    • IN Fate Mapping
    • Progenitor Zones/Stem Cell Biology in the Ganglionic Eminences
    • Functions of TFs Expressed in Migratory and Post-Migratory Immature INs
    • Genomic Approaches to Understand Transcriptional Control of IN Development
    • Conclusion
    • Disclosure Statement
    • Acknowledgments
    • References
  • 48. GABA_A Receptors, Seizures, and Epilepsy
    Richard W. Olsen, Martin Wallner, and Michael A. Rogawski.
    • Abstract
    • GABA_A Receptors in Epilepsy and as Therapeutic Targets
    • GABAR Structure
    • GABAR Subtypes
    • Targeting GABAR Subtypes for Epilepsy Therapy
    • Tolerance
    • Treatment of Epilepsy Comorbidities
    • EtOH-Induced Plasticity of GABAR-Mediated Inhibition at the Gene Expression and Protein Levels
    • Synaptic Matrix Tethering with Neuroligin-2, Gephyrin, and Collybistin; Role of LHFPL4
    • Activation of Extrasynaptic δ-GABAR Induces Spike-Wave Seizures
    • Advances in GABAR Structural Pharmacology Relevant to Pentobarbital, Propofol, and Etomidate
    • Neuroactive Steroids
    • Benzodiazepines
    • Stiripentol
    • Optogenetics and Chemogenetics
    • Conclusion and Future Directions
    • Disclosure Statement
    • References
  • 49. Gene–Genome Interactions: Understanding Complex Molecular Traits in Epilepsy
    Katja Kobow and John Matthew Mahoney.
    • Abstract
    • Complex Molecular Networks in Epilepsy
    • The Growing Epilepsy Genome
    • Studying the “Multiome”
    • Single-Cell Analysis
    • 3D Genome Conformation
    • Genetics 3.0—Artificial Intelligence and Deep Learning
    • The Next Ten Years
    • References
• Section 6. Progressive Myoclonus Epilepsies
  Antonio V. Delgado-Escueta, José M. Serratosa, and Berge A. Minassian.
  • 50. The Neuronal Ceroid Lipofuscinoses
    Sara E. Mole.
    • Abstract
    • Introduction
    • Genetics
    • Epidemiology
    • Clinical Features
    • Morphology
    • Molecular Basis of Disease
    • Diagnosis
    • Care Management
    • Therapy
    • Conclusions and Future Directions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 51. Progressive Myoclonus Epilepsy: Unverricht-Lundborg Disease
    Saara Tegelberg, Tarja Joensuu, and Anna-Elina Lehesjoki.
    • Abstract
    • Introduction
    • The Cystatin B Gene and Protein
    • Cystatin B–Deficient Mouse Model for EPM1
    • Disease Mechanisms
    • Oxidative Stress and Apoptotic Cell Death
    • Disclosure Statement
    • References
  • 52. Strategies on Gene Therapy in Progressive Myoclonus Epilepsies
    Saima Kayani, Emrah Gumusgoz, Berge A. Minassian, and Alison Dolce.
    • Abstract
    • Introduction
    • Gene Therapy with Particularities to Progressive Myoclonus Epilepsy
    • Conclusion
    • References
  • 53. Therapeutic Window for the Treatment of Lafora Disease
    Olga Varea, Joan J. Guinovart, and Jordi Duran.
    • Abstract
    • Brain Glycogen
    • Lafora Disease
    • Pathological Contribution of Glycogen in the LD Brain
    • Targeting Glycogen to Treat LD
    • Malin Gene Replacement Therapy to Treat LD
    • New Challenges and Perspectives Using MGS-Based Suppression or Malin-Restoration Approaches
    • Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 54. Progressive Myoclonus Epilepsy of Lafora: Treatment with Metformin
    José M. Serratosa, Daniel F. Burgos, Luis Zafra-Puerta, Nerea Iglesias-Cabeza, Pascual Sanz, and Marina P. Sánchez.
    • Abstract
    • Introduction
    • Proposed Mechanism of Action of Metformin
    • Metformin as a Neuroprotective Agent in Epilepsy
    • Metformin in Lafora Disease
    • Acknowledgments
    • Disclosure Statement
    • References
  • 55. Treating Lafora Disease with an Antibody-Enzyme Fusion
    Matthew S. Gentry, Kia H. Markussen, Ramon C. Sun, and Craig W. Vander Kooi.
    • Abstract
    • The Problem: Lafora Bodies Drive Epilepsy, Neurodegeneration, and Inflammation
    • Glycogen
    • The Solution: Novel Antibody-Enzyme Fusions Clear LBs
    • Assessing Brain Function via Metabolomics
    • Next Steps
    • Acknowledgments
    • Disclosure Statement
    • References
  • 56. Antisense Oligonucleotide Therapy for Progressive Myoclonus Epilepsies
    Silvia Nitschke and Berge A. Minassian.
    • Abstract
    • Progressive Myoclonus Epilepsies—A Brief Overview
    • Antisense Oligonucleotides and Their Different Modes of Action
    • ASO Strategies to Treat PME Disorders
    • Conclusions and Future Perspectives
    • Acknowledgments
    • References
• Section 7. Comorbidities of Epileptic Networks
  Jeffrey L. Noebels.
  • 57. Dissecting Epileptic and Cognitive Network Dysfunction in Epilepsy
    Pierre-Pascal Lenck-Santini and Gregory Holmes.
    • Abstract
    • Introduction
    • Memory Processes
    • Measuring the Functional Integrity of Neuronal Networks
    • Probing Brain Functions through Single-Unit Activity
    • Functional Mechanisms of Cognitive Impairment in Epilepsy
    • Conclusion and Perspectives
    • Acknowledgments
    • Conflict of Interest
    • References
  • 58. Attention-Deficit Disorders and Epilepsy
    Atul Maheshwari.
    • Abstract
    • Epilepsy and ADHD—Clinical Background and Genetics
    • Pathophysiologic Insights from Rodent Models of Epilepsy and ADHD
    • Insights into Current and Future Treatment of Attention Disorders in Epilepsy
    • Conclusion
    • References
  • 59. What Rodent Models Teach Us about the Association of Autism and Epilepsy
    Peyman Golshani.
    • Abstract
    • The Association of Autism and Epilepsy
    • The Role of Animal Models for Studying Autism/Epilepsy Syndromes
    • Dravet Syndrome: An Ion Channelopathy Causing Refractory Seizures, Cognitive Deficits, and Autism
    • Calcium Channelopathies
    • Potassium Channels: Kv4.2 and Kv7.2
    • CNTNAP2
    • Do Seizures during Development Cause Impairments in Social Behavior?
    • Future Directions
    • References
  • 60. Artificial Intelligence–Guided Behavioral Phenotyping in Epilepsy
    Tilo Gschwind and Ivan Soltesz.
    • Abstract
    • Introduction
    • Analyzing Behavior Starts with Tracking
    • Machine Learning and Deep Learning Revolutionized Animal Motion Tracking
    • Quantifying Behavior
    • Conclusion and Future Directions for Basic Epilepsy Research
    • Acknowledgments
    • Disclosure Statement
    • References
  • 61. Mechanisms of Depression in the Epileptic Brain
    Nigel C. Jones and Jamie Maguire.
    • Abstract
    • Epilepsy and Depression Comorbidity
    • Phenomenology
    • Management and Treatment
    • Depression and Vulnerability to Epilepsy
    • Epilepsy and Vulnerability to Depression
    • Mechanisms of Depression
    • Potential Mechanisms Mediating Comorbid Depression and Epilepsy
    • Summary
    • Acknowledgments
    • Disclosure Statement
    • References
  • 62. Heterogeneous Mechanisms of Spreading Depolarization and Seizures
    Isamu Aiba.
    • Abstract
    • Introduction
    • SD and Seizure Generation in Acute, Subacute, and Chronic Conditions
    • Summary
    • Acknowledgments
    • Disclosure Statement
    • References
  • 63. Genetic and Cellular Mechanisms Underlying SUDEP Risk
    Jeffrey L. Noebels.
    • Abstract
    • Introduction
    • The MORTEMUS Study Defines a Common Temporal Framework for Nocturnal Sudden Death
    • The MORTEMUS Pattern and Timetable Have Mechanistic Implications
    • Ictal Asystoles, Ictal Apneas, and Postictal Cortical EEG Suppression Are Unreliable SUDEP Biomarkers
    • Atypical SUDEP Patterns: Parallels with SCD, SIDS, and SUDY
    • Monogenic SUDEP Risk
    • The Neurocardiac Gene Hypothesis for SUDEP
    • Potassium Channels
    • Sodium Channels
    • Ryanodine Receptor
    • SUDEP Gene Diversity
    • Monogenic Neurorespiratory Syndromes
    • Gene-Specific Longevity Profiles: SD50
    • Epistatic Interactions among SUDEP Genes Impact Survival
    • Conditional Genetic Dissection of Critical SUDEP Pathways
    • Progressive Central and Cardiac Pathology and SUDEP Risk
    • Diurnal Rhythm and SUDEP
    • Brainstem Spreading Depolarization
    • Brainstem SD Is Linked to Postictal Cardiorespiratory Collapse in Mouse SUDEP Models
    • In Vivo SD Imaging
    • Seizure-SD Coupling
    • The Perilous Genetic Landscape of SUDEP
    • SUDEP: Gene-Guided Research and Interventions
    • Summary
    • Acknowledgments
    • References
• Section 8. Epilepsy Therapeutics
  Michael A. Rogawski.
  • 64. New Models for Assessment of Antiseizure Activity
    Cameron S. Metcalf, Peter J. West, Sharon F. Edwards, and Karen S. Wilcox.
    • Abstract
    • Introduction
    • Zebrafish and Other Model Organisms
    • Drosophila melanogaster Models of Epilepsy
    • Mouse Models of Genetic Epilepsy and Therapy Development
    • Theiler’s Murine Encephalomyelitis Virus Mouse Model
    • Intra-Amygdala Kainate and Intra-Hippocampal Kainate Mouse Models
    • Induced Pluripotent Stem Cells and the Future
    • Summary and Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 65. Disease Biology Factors Accounting for Epilepsy Severity: An Updated Conceptual Framework for New Drug Discovery
    Stefanie Dedeurwaerdere, Vincenzo Marra, and Michael R. Johnson.
    • Abstract
    • Call for Paradigm Shift Toward Treating Disease Biology
    • Drug-Resistant Epilepsy: Time to Break with Traditional Views
    • Concept of Intrinsic Epilepsy Severity Index
    • Future Technologies Will Drive Better Understanding of Neurobiological Factors Contributing to the Epilepsy Severity Index
    • Intrinsic Disease Severity Concept Provides a Holistic View to Drug Resistance
    • Targeting Intrinsic Epilepsy Severity as an Approach to Achieve Disease Control
    • Conclusion
    • Acknowledgments
    • Disclosure
    • References
  • 66. Animal Models of Pharmacoresistant Epilepsy
    Michelle Guignet and H. Steve White.
    • Abstract
    • Introduction
    • 6 Hz Psychomotor Seizure Model
    • Lamotrigine-Resistant Kindled Rodent Model
    • Phenytoin-Resistant Kindled Rat Model
    • Post–Status Epilepticus Models of Spontaneous Recurrent Seizures
    • Conclusion
    • References
  • 67. Drug Combinations for Antiepileptogenesis
    Wolfgang Löscher.
    • Abstract
    • Introduction
    • Single Drug versus Drug Combinations for Antiepileptogenesis
    • Efficacy of Drug Combination to Prevent or Modify the Development of Epilepsy
    • Systematic Evaluation of Drug Combinations for Antiepileptogenesis
    • Effects on Diverse versus Similar Targets for Antiepileptogenesis
    • Top-Down versus Bottom-Up Target-Based Approaches in Identifying New Antiepileptogenic Therapies
    • Future Advancements in the Search for Synergistic Antiepileptogenic Drug Combinations
    • Conclusions and Outlook
    • Acknowledgments
    • Disclosure Statement
    • References
  • 68. Prophylaxis of Epileptogenesis in Injury and Genetic Epilepsy Models
    David A. Prince and Feng Gu.
    • Abstract
    • Gabapentinoids, Excitatory Synapse Formation, and Antiepileptogenesis
    • Antiepileptogenesis in a Genetic, Noninjury Model of Epilepsy with Enhanced Excitatory Connectivity
    • Antiepileptogenesis in Posttraumatic Epilepsy and a Genetic Epilepsy Model with Reduced Inhibitory Interneuronal Function
    • Unresolved Issues
    • Acknowledgments
    • Disclosure Statement
    • References
  • 69. Management of Febrile Status Epilepticus: Past, Present, and Future
    Megan M. Garcia-Curran and Tallie Z. Baram.
    • Abstract
    • Introduction
    • Outcomes Following Febrile Status Epilepticus: Risk of Epilepsy
    • Outcomes Following Febrile Status Epilepticus: Cognitive Deficits
    • Pharmacologic Management of FSE: Past and Present
    • Neuroimaging after FSE to Predict Clinical Outcomes
    • Future Treatments to Prevent Long-Term Neurological Changes Following FSE
    • The Future of FSE and Its Treatment
    • Acknowledgments
    • References
  • 70. Excitatory Transmission in Status Epilepticus
    Suchitra Joshi and Jaideep Kapur.
    • Abstract
    • Introduction
    • Cholinergic Agents and Glutamate Analogs Induce Status Epilepticus
    • Glutamate Receptors
    • Glutamate Receptor Expression in the Brain
    • Glutamate Receptor Plasticity during SE
    • Glutamate Receptor Antagonists in the Treatment of SE: Studies in Experimental Animals
    • Glutamate Excitotoxicity and Cell Death
    • NMDA Receptors Regulate the Plasticity of GABA-A and AMPA Receptors during SE
    • NMDA Receptors Regulate Epileptogenesis
    • Glutamate Receptor Antagonists in the Treatment of SE
    • Conclusions
    • References
  • 71. Ionic Mechanisms of Ictogenic Disinhibition: All GABA Signaling Is Local
    Kevin J. Staley.
    • Abstract
    • Introduction
    • Physiology
    • Pathology
    • References
  • 72. Epileptogenic Channelopathies Guide Design of NBI-921352, a Highly Isoform-Selective Inhibitor of NaV1.6
    J. P. Johnson, Alison J. Cutts, James R. Empfield, and Charles J. Cohen.
    • Abstract
    • Introduction
    • Na_V Cellular and Subcellular Distribution
    • Genetic Channelopathies Guide a Preferred Selectivity Profile for Antiseizure Medications
    • Designing a New Class of Isoform-Selective Sodium Channel Inhibitors
    • NBI-921352, the First Isoform-Selective Inhibitor of Na_V1.6
    • Like Nonselective Na_V Inhibitor ASMs That Bind the Pore Domain, NBI-921352 Is a State-Dependent Inhibitor
    • NBI-921352 Inhibits Persistent and Resurgent Currents from Mutant Na_V1.6 Channels
    • NBI-921352 Inhibits Electrically Induced Seizures in Scn8a N1768D/+ Mice
    • Concentration Dependence of NBI-921352 in Comparison to Common ASMs
    • NBI-921352 Inhibits Electrically Induced Seizures in Wild-Type Mice and Rats
    • Efficacious Concentrations of NBI-921352 Are Well Separated from Concentrations That Provoke Behavioral Signs
    • In Vitro Na_V1.6 Inhibition Predicts In Vivo Efficacy
    • Conclusions
    • References
  • 73. Purinergic Signaling in Epilepsy
    Tobias Engel and Nicholas Dale.
    • Abstract
    • Purinergic Signaling in the Brain
    • Targeting Purinergic Receptors for Seizure Control and the Treatment of Epilepsy
    • Purines as Diagnostics for Epilepsy
    • Conclusion
    • Acknowledgments
    • Disclosure Statement
    • References
  • 74. Anti-inflammatory Strategies for Disease Modification: Focus on Therapies Close to Clinical Translation
    Annamaria Vezzani, Silvia Balosso, Nicholas H. Varvel, and Ray Dingledine.
    • Abstract
    • Introduction
    • Interference with the IL-1beta-IL-1R1 Axis
    • Clinical Studies with Anti-IL-1beta Treatments
    • Arachidonic Acid and COX-2 Signaling Pathways
    • Dexamethasone
    • Interference with Leukocyte-Endothelial Cell Interaction by Natalizumab
    • Statins
    • Combinatorial Anti-inflammatory Therapy
    • Summary and Conclusions
    • Acknowledgments
    • Disclosure Statement
    • References
  • 75. Targeted Augmentation of Nuclear Gene Output (TANGO)
    Lori L. Isom and Kelly G. Knupp.
    • Abstract
    • Dravet Syndrome: An Intractable Developmental and Epileptic Encephalopathy
    • Identification of Nonsense-Mediated Decay, or Poison, Exons in SCN1A
    • TANGO: A Therapeutic Strategy That Takes Advantage of NMD Exons
    • Noncoding Sequences in SCN1A
    • Other Therapeutic Strategies on the Horizon
    • Rett Syndrome and Angelman Syndrome—Other DEEs with Unique Challenges
    • Pros and Cons of Gene Regulation Therapy
    • Conclusion
    • Disclaimer Statement
    • References
  • 76. Gene Therapy for Epilepsy
    Kimberly Goodspeed, Dallas Armstrong, Andrea Boitnott, Alison Dolce, Qinglan Ling, and Steven J. Gray.
    • Abstract
    • Introduction
    • Overview of Gene Therapy
    • Gene Therapy in Epilepsy
    • Conclusion
    • References
  • 77. Gene Therapy for Refractory Epilepsy
    Dimitri M. Kullmann.
    • Abstract
    • Introduction
    • Viral Vectors
    • Promoters
    • Transgenes: Manipulation of the Excitation/Inhibition (E/I) Balance
    • Regulated Gene Therapy
    • Upregulation of Endogenous Gene Expression
    • Neurotrophic Factors
    • Monogenic Epilepsies
    • Clinical Translation
    • Conclusions
    • Disclosure Statement
    • References
  • 78. Cell Therapy for Treatment of Epilepsy
    Sonja Bröer and Daniel Vogt.
    • Abstract
    • Introduction
    • The Route to Clinical Studies
    • Proof-of-Concept Studies
    • Delivering GABA: Cell Resources and Progress
    • Functional Properties of IN
    • Preclinical Studies with Cell Transplantation
    • Safety
    • Where Are We Now?
    • Conclusion
    • Acknowledgments
    • Disclosure Statement
    • References
  • 79. Mechanisms of Ketogenic Diet Action
    Robin S. B. Williams, Detlev Boison, Susan A. Masino, and Jong M. Rho.
    • Abstract
    • Introduction
    • Historical and Clinical Perspectives
    • Mechanistic Studies in the Early Renaissance Era
    • Insights at the Close of the First Century of Use
    • Beyond Epilepsy
    • 2021 National Institutes of Health Ketogenic Diet Workshop
    • Conclusions
    • Acknowledgments
    • Competing Interests
    • References

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