Basic Neurophysiology of Brain0 Dr. Chintan Parmar0 Dept. of Physiology,

0 KIMS & RF0 Dt. 25/08/2014

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Outline0 Definitions0 Basic Anatomy of Cortex0 Synapse0 Action Potential0 Cellular Mechanisms of Seizure Generation0 Focal Seizure Initiation 0 Seizure Propagation0 Epileptogenesis

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Definitions0A seizure is the clinical manifestation of an abnormal,

excessive, hyper synchronous discharge of a population of cortical neurons.

0Epilepsy is a disorder of the CNS characterized by recurrent seizures unprovoked by an acute systemic or neurologic insult.

0Epileptogenesis is the sequence of events that turns a normal neuronal network into a hyper excitable network.

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Basic Anatomy of Cortex0The human cerebral cortex consists of 3 to 6 layers of

neurons.

0The phylogenetically oldest part of the cortex (archipallium) has 3 distinct neuronal layers, and is represented by the hippocampus, which is found in the medial temporal lobe.

0The majority of the cortex (neocortex or neopallium) has 6 distinct cell layers and covers most of the surface of the cerebral hemispheres.

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Basic Anatomy of Cortex0The hippocampus consists of three major regions:

subiculum, hippocampus proper and dentate gyrus.

0The hippocampus and dentate gyrus have a 3 layered cortex.

0The subiculum is the transition zone from the 3 to the 6 layered cortex.

0Important regions of the hippocampus proper include CA1, CA 2, CA 3 & CA 4.

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Synapse

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0 The basic mechanism of neuronal excitability is the action potential.

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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 ion

concentrations in favor of membrane depolarization.

0A hyperexcitable state can also result when several synchronous subthreshold excitatory stimuli occur, allowing their temporal summation in the post synaptic neurons.

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Cellular Mechanisms 0 Neuronal (Intrinsic) Factors Modifying Neuronal Excitability

0 The type, number and distribution of voltage and ligand gated channels

0 Such channels determine the direction, degree, and rate of changes in the transmembrane potential, which in turn determine whether an action potential occurs or not

0 Biochemical modification of receptors

0 Activation of second-messenger systems

0 Modulating gene expression by RNA editing25/08/2014 KIMS & RF, Symposium on Epilepsy 12

Cellular Mechanisms 0Extra-Neuronal (Extrinsic) Factors Modifying

Neuronal Excitability

0Changes in extracellular ion concentration due to variations in the volume of the extracellular space

0Remodeling of synaptic contacts

0Modulating transmitter metabolism by glial cells

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Cellular Mechanisms 0 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 in distant areas of the brain.

0 Interneurons (e.g., basket cells) are generally considered to be local-circuit cells which influence the activity of nearby neurons.

0 Most principal neurons form excitatory synapses on post-synaptic neurons, while most interneurons form inhibitory synapses on principal cells or other inhibitory neurons.

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Cellular Mechanisms 0Network Organization Influences Neuronal Excitability

0In the dentate gyrus, afferent connections to the network can directly activate the projection cell (e.g., pyramidal cells).

0The input can also directly activate local interneurons (bipolar and basket cells),

0These cells may inhibit projection cells in the vicinity (feed-forward inhibition).

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Cellular Mechanisms 0Network Organization Influences Neuronal

Excitability

0The projection neuron may in turn activate the interneurons which in turn act on the projection neurons (feedback inhibition).

0Sprouting of excitatory axons to make more numerous connections can increase excitability of the network of connected neurons

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Focal Seizure Initiation0 The hypersynchronous discharges that occur during a seizure

may begin in a very discrete region of cortex and then spread to neighboring regions.

0 Seizure initiation is characterized by two concurrent events: 0 1) high-frequency bursts of action potentials, and 0 2) hypersynchronization of a neuronal population

0 Paroxysmal depolarizing shift - sustained neuronal depolarization resulting in a burst of action potentials, a plateau-like depolarization associated with completion of the action potential burst, and then a rapid repolarization followed by hyperpolarization

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Seizure Propagation0 The propagation of bursting activity is normally prevented by intact

hyperpolarization and a region of surrounding inhibition created by inhibitory neurons.

0 With sufficient activation there is a recruitment of surrounding neurons.

0 Repetitive discharges lead to: 0 1) an increase in extracellular K+, which blunts the extent of hyperpolarizing

outward K+ currents, tending to depolarize neighboring neurons; 0 2) accumulation of Ca++ in presynaptic terminals, leading to enhanced

neurotransmitter release; and 0 3) depolarization-induced activation of the NMDA subtype of the excitatory

amino acid receptor, which causes more Ca++ influx and neuronal activation.

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Epileptogenesis0 Approximately 50% of patients who suffer a severe head injury will

develop a seizure disorder.

0 In a significant number of these patients, the seizures will not become clinically evident for months or years.

0 This "silent period" after the initial injury indicates that in some cases the epileptogenic process involves a gradual transformation of the neural network over time.

0 Changes occurring during this period could include delayed necrosis of inhibitory interneurons (or the excitatory interneurons driving them), or sprouting of axonal collaterals leading to reverberating, or self-reinforcing, circuits.

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Epileptogenesis0 An important experimental model of Epileptogenesis is kindling

0 Daily, subconvulsive stimulation (electrical or chemical) of certain brain regions such as the hippocampus or amygdala result in electrical afterdischarges, eventually leading to stimulation-induced clinical seizures, and in some instances, spontaneous seizures.

0 This change in excitability is permanent and presumably involves long-lasting biochemical and/or structural changes in the CNS.

0 Alterations in glutamate channel properties, selective loss of neurons, and axonal reorganization.

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THANQ…

Any Question ???