Neurophysiology of epilepsy

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  • 1. Basic Neurophysiology of Brain0 Dr. Chintan Parmar0 Dept. of Physiology,0 KIMS & RF0 Dt. 25/08/201425/08/2014 1

2. Outline0 Definitions0 Basic Anatomy of Cortex0 Synapse0 Action Potential0 Cellular Mechanisms of Seizure Generation0 Focal Seizure Initiation0 Seizure Propagation0 Epileptogenesis25/08/2014 KIMS & RF, Symposium on Epilepsy 2 3. Definitions0A seizure is the clinical manifestation of an abnormal,excessive, hyper synchronous discharge of a populationof cortical neurons.0Epilepsy is a disorder of the CNS characterized byrecurrent seizures unprovoked by an acute systemicor neurologic insult.0Epileptogenesis is the sequence of events that turns anormal neuronal network into a hyper excitablenetwork.25/08/2014 KIMS & RF, Symposium on Epilepsy 3 4. Basic Anatomy of Cortex0The human cerebral cortex consists of 3 to 6 layers ofneurons.0The phylogenetically oldest part of the cortex(archipallium) has 3 distinct neuronal layers, and isrepresented by the hippocampus, which is found in themedial temporal lobe.0The majority of the cortex (neocortex or neopallium)has 6 distinct cell layers and covers most of thesurface of the cerebral hemispheres.25/08/2014 KIMS & RF, Symposium on Epilepsy 4 5. 25/08/2014KIMS & RF, Symposium onEpilepsy5 6. Basic Anatomy of Cortex0The hippocampus consists of three major regions:subiculum, hippocampus proper and dentate gyrus.0The hippocampus and dentate gyrus have a 3 layeredcortex.0The subiculum is the transition zone from the 3 to the 6layered cortex.0Important regions of the hippocampus proper includeCA1, CA 2, CA 3 & CA 4.25/08/2014 KIMS & RF, Symposium on Epilepsy 6 7. 25/08/2014 KIMS & RF, Symposium on Epilepsy 7 8. 25/08/2014KIMS & RF, Symposium onEpilepsy8 9. Synapse25/08/2014KIMS & RF, Symposium onEpilepsy9 10. 0 The basic mechanism of neuronal excitability is the actionpotential.25/08/2014 KIMS & RF, Symposium on Epilepsy 10 11. Action Potential0A hyperexcitable state can result from;0increased excitatory synaptic neurotransmission,0decreased inhibitory neurotransmission,0an alteration in voltage-gated ion channels,0an alteration of intra- or extra-cellular ionconcentrations in favor of membranedepolarization.0A hyperexcitable state can also result when severalsynchronous subthreshold excitatory stimuli occur,allowing their temporal summation in the postsynaptic neurons.25/08/2014 KIMS & RF, Symposium on Epilepsy 11 12. Cellular Mechanisms0 Neuronal (Intrinsic) Factors Modifying Neuronal Excitability0 The type, number and distribution of voltage and ligand gatedchannels0 Such channels determine the direction, degree, and rate ofchanges in the transmembrane potential, which in turndetermine whether an action potential occurs or not0 Biochemical modification of receptors0 Activation of second-messenger systems0 Modulating gene expression by RNA editing25/08/2014 KIMS & RF, Symposium on Epilepsy 12 13. Cellular Mechanisms0Extra-Neuronal (Extrinsic) Factors ModifyingNeuronal Excitability0Changes in extracellular ion concentration due tovariations in the volume of the extracellular space0Remodeling of synaptic contacts0Modulating transmitter metabolism by glial cells25/08/2014 KIMS & RF, Symposium on Epilepsy 13 14. Cellular Mechanisms0 The cortex includes two general classes of neurons.0 The projection, or principal neurons (e.g., pyramidal neurons)are cells that "project" or send information to neurons located indistant areas of the brain.0 Interneurons (e.g., basket cells) are generally considered to belocal-circuit cells which influence the activity of nearby neurons.0 Most principal neurons form excitatory synapses on post-synapticneurons, while most interneurons form inhibitorysynapses on principal cells or other inhibitory neurons.25/08/2014 KIMS & RF, Symposium on Epilepsy 14 15. Cellular Mechanisms0Network Organization Influences Neuronal Excitability0In the dentate gyrus, afferent connections to the networkcan directly activate the projection cell (e.g., pyramidalcells).0The input can also directly activate local interneurons(bipolar and basket cells),0These cells may inhibit projection cells in the vicinity (feed-forwardinhibition).25/08/2014 KIMS & RF, Symposium on Epilepsy 15 16. Cellular Mechanisms0Network Organization Influences NeuronalExcitability0The projection neuron may in turn activate theinterneurons which in turn act on the projectionneurons (feedback inhibition).0Sprouting of excitatory axons to make morenumerous connections can increase excitability ofthe network of connected neurons25/08/2014 KIMS & RF, Symposium on Epilepsy 16 17. Focal Seizure Initiation0 The hypersynchronous discharges that occur during a seizuremay begin in a very discrete region of cortex and then spread toneighboring regions.0 Seizure initiation is characterized by two concurrent events:0 1) high-frequency bursts of action potentials, and0 2) hypersynchronization of a neuronal population0 Paroxysmal depolarizing shift - sustained neuronaldepolarization resulting in a burst of action potentials, a plateau-likedepolarization associated with completion of the actionpotential burst, and then a rapid repolarization followed byhyperpolarization25/08/2014 KIMS & RF, Symposium on Epilepsy 17 18. 25/08/2014KIMS & RF, Symposium onEpilepsy18 19. Seizure Propagation0 The propagation of bursting activity is normally prevented by intacthyperpolarization and a region of surrounding inhibition createdby inhibitory neurons.0 With sufficient activation there is a recruitment of surroundingneurons.0 Repetitive discharges lead to:0 1) an increase in extracellular K+, which blunts the extent ofhyperpolarizing outward K+ currents, tending to depolarizeneighboring neurons;0 2) accumulation of Ca++ in presynaptic terminals, leading to enhancedneurotransmitter release; and0 3) depolarization-induced activation of the NMDA subtype of theexcitatory amino acid receptor, which causes more Ca++ influx andneuronal activation.25/08/2014 KIMS & RF, Symposium on Epilepsy 19 20. Epileptogenesis0 Approximately 50% of patients who suffer a severe head injury willdevelop a seizure disorder.0 In a significant number of these patients, the seizures will not becomeclinically evident for months or years.0 This "silent period" after the initial injury indicates that in some casesthe epileptogenic process involves a gradual transformation of theneural network over time.0 Changes occurring during this period could include delayed necrosisof inhibitory interneurons (or the excitatory interneurons drivingthem), or sprouting of axonal collaterals leading to reverberating, orself-reinforcing, circuits.25/08/2014 KIMS & RF, Symposium on Epilepsy 20 21. Epileptogenesis0 An important experimental model of Epileptogenesis is kindling0 Daily, subconvulsive stimulation (electrical or chemical) of certainbrain regions such as the hippocampus or amygdala result inelectrical afterdischarges, eventually leading to stimulation-inducedclinical seizures, and in some instances, spontaneousseizures.0 This change in excitability is permanent and presumably involveslong-lasting biochemical and/or structural changes in the CNS.0 Alterations in glutamate channel properties, selective loss ofneurons, and axonal reorganization.25/08/2014 KIMS & RF, Symposium on Epilepsy 21 22. THANQAny Question ???