Histology of cerebral cortex

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This pp was created for a PBL problem based on a brief overview on the histology of the cerebral cortex, epilepsy and EEG procedure and the mechanism of action of anticonvulsants

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Histology of cerebral cortex

  1. 1. Problem 1: A strange fever By Aneesa Naadira Khan“A person with a new idea is a crank until the idea succeeds.” Call me crazy
  2. 2. Objective 1Briefly describe the histology of the cerebral cortex
  3. 3. The cerebral cortex Has a thickness varying 1 to 4mm Is composed of glial cells and neurons Has six layers: I Molecular layer II External granular layer III External pyramidal layer IV Internal granular layer V Internal pyramidal layer VI Multiform (polymorphic layer)
  4. 4.  Layer 1 consists mainly of apical dendrites from pyramidal cells from lower layers — plus axons synapsing on those dendrites. It contains almost no neuron cell bodies. Layer 2 contains many small densely-packed pyramidal neurons — giving it a granular appearance. Layer 3 contains medium-sized pyramidal neurons which send outputs to other cortical areas. Layer 4 contains many spiny stellate (excitatory) interneurons Layer 5 contains the largest pyramidal neurons, which send outputs to the brain stem and spinal cord (the pyramidal tract) Layer 6 consists of pyramidal neurons and neurons with spindle-shaped cell bodies.
  5. 5.  6 layers of the cerebral cortex: Molecular (plexiform) layer  apical dendrites of pyramidal cells  large no. of synapses happen here OUTER granular layer  stellate cells OUTER pyramidal cell layer  pyramidal cells smaller INNER granular layer  closely packed stellate cells  horizontal fibres (of Baillarger) INNER pyramidal cell later (ganglionic layer)  large pyramidal cells  particularly in motor area  inner fibres of Baillarger Multiform cell layer  fusiform cells  many nerve fibres entering white matter
  6. 6. Stellate (Granule) Cells  These come in a wide assortment of shapes.  They are typically small (< 10 micrometres) multipolar neurons.  Their short axons do not leave the cortex.  Stellate cells are the principal interneurons of the neocortex.
  7. 7. Pyramidal Cells These cells are shaped as they are named. Pyramidal cells range in size from 10 micrometres in diameter to 70-100 micrometres of the giant pyramidal cells (Betz cells) of the motor cortex. A long apical dendrite leaves the top of each pyramidal cell and ascends vertically to the cortical surface. A series of basal dendrites emerges from nearer the base of the cell and spreads out horizontally. The apical dendrites of pyramidal cells are studded with dendritic spines. These are numerous small projections that are the preferential site of synaptic contact. It has been suggested that dendritic spines may be the sites of synapses that are selectively modified as a result of learning. Most or all pyramidal ells have long axons that leave the cortex to reach either other cortical areas or to various subcortical sites. Therefore, pyramidal cells are the principal output neurons.
  8. 8. Fusiform Cells These are found in the deepest cortical layer. They are spindle-shaped with a tuft of dendrites emerging from each end of the spindle. They are, however, otherwise like pyramidal cells with an axon that leaves the cortex.
  9. 9. Objective 2Describe typical brain waves seen on the eeg and howit is conducted
  10. 10. What is EEG? An electroencephalogram (EEG) is a painless procedure that uses small, flat metal discs (electrodes) attached to your scalp to detect electrical activity in your brain. Your brain cells communicate via electrical impulses and are active all the time, even when youre asleep. This activity shows up as wavy lines on an EEG recording.From : myoclinic.com
  11. 11. During the procedure A standard noninvasive EEG takes about 1 hour. The patient will be positioned on a padded bed or table, or in a comfortable chair. To measure the electrical activity in various parts of the brain, a nurse or EEG technician will attach 16 to 20 electrodes to the scalp. The brain generates electrical impulses that these electrodes will pick up. To improve the conduction of these impulses to the electrodes, a gel will be applied to them. Then a temporary glue will be used to attach them to the skin. No pain will be involved. The electrodes only gather the impulses given off by the brain and do not transmit any stimulus to the brain. The technician may tell the patient to breathe slowly or quickly and may use visual stimuli such as flashing lights to see what happens in the brain when the patient sees these things. The brains electrical activity is recorded continuously throughout the exam on special EEG paper.
  12. 12. Normal brain waves Alpha waves occur at a frequency of 8 to 12 cycles per second in a regular rhythm. They are present only when you are awake but have your eyes closed. Usually they disappear when you open your eyes or start mentally concentrating. Beta waves occur at a frequency of 13 to 30 cycles per second. They are usually associated with anxiety, depression, or the use of sedatives. Theta waves occur at a frequency of 4 to 7 cycles per second. They are most common in children and young adults. Delta waves occur at a frequency of 0.5 to 3.5 cycles per second. They generally occur only in young children during sleep.
  13. 13.  Beta waves (15-30 oscillations (or waves) per second (Hz)). This is the brain rhythm in the normal wakeful state associated with thinking, conscious problem solving and active attention directed towards the outer world. You are most likely in the "beta state" while you are reading this. Alpha waves (9-14 Hz). When you are truly relaxed, your brain activity slows from the rapid patterns of beta into the more gentle waves of alpha. Fresh creative energy begins to flow, fears vanish and you experience a liberating sense of peace and well-being. The "alpha state" is where meditation starts and you begin to access the wealth of creativity that lies just below our conscious awareness. It is the gateway that leads into deeper states of consciousness. Theta waves (4-8 Hz). Going deeper into relaxation and meditation, you enter the "theta state" where brain activity slows almost to the point of sleep. Theta brings forward heightened receptivity, flashes of dreamlike imagery, inspiration, and,sometimes, your long-forgotten memories. It can also give you a sensation of "floating". Theta is one of the more elusive and extraordinary realms we can explore. It is also known as the twilight state which we normally only experience fleetingly as we rise up out of the depths of delta upon waking, or drifting off to sleep. In theta, we are in a waking dream, and we are receptive to information beyond our normal conscious awareness. Some people believe that theta meditation awakens intuition and other extrasensory perception skills. Delta waves (1-3 Hz). This slowest of brainwave activity is found during deep, dreamless sleep. It is also sometimes found in very experienced meditators.
  14. 14. Objective 3Explain the mechanism of action of anticonvulsants
  15. 15. Predominant MOA of anticonvulsantdrugs
  16. 16. Phenytoin Alters Na , K , and Ca conductance, membrane potentials and the concentrations of amino acids and the neurotransmitters norepinephrine, acetocholine and y-aminobutyric acid (GABA) Blocks sustained high-frequency repetitive firing of action potentials. It is a use-dependent effect on Na conductance arising from preferential binding to and prolongation of the inactivated state of the Na channel
  17. 17. Na channel blockers Some antiepileptic drugs stabilize inactive configuration of sodium (Na+) channel, preventing high- frequency neuronal firing. During an action potential, these channels exist in the active state and allow influx of sodium ions. Once the activation or stimulus is terminated, a percentage of these sodium channels become inactive for a period known as the refractory period. With constant stimulus or rapid firing, many of these channels exist in the inactive state, rendering the axon incapable of propagating the action potential. AEDs that target the sodium channels prevent the return of these channels to the active state by stabilizing them in the inactive state. In doing so, they prevent repetitive firing of the axons
  18. 18. Na channel blockers Sodium channel blockade is the most common and best-characterized mechanism of currently available antiepileptic drugs (AEDs). AEDs that target sodium channels prevent the return of the channels to the active state by stabilizing the inactive form. In doing so, repetitive firing of the axons is prevented. Presynaptic and postsynaptic blockade of sodium channels of the axons causes stabilization of the neuronal membranes, blocks and prevents posttetanic potentiation, limits the development of maximal seizure activity, and reduces the spread of seizures.
  19. 19. Calcium channel blockers Low-voltage calcium (Ca2+) currents (T- type) are responsible for rhythmic thalamocortical spike and wave patterns of generalized absence seizures. Some antiepileptic drugs lock these channels, inhibiting underlying slow depolarizations necessary to generate spike-wave bursts.Calcium channels exist in 3 known forms in the human brain: L, N, and T. Thesechannels are small and are inactivated quickly. The influx of calcium currents in theresting state produces a partial depolarization of the membrane, facilitating thedevelopment of an action potential after rapid depolarization of the cell.Calcium channels function as the " pacemakers " of normal rhythmic brain activity.This is particularly true of the thalamus. T-calcium channels have been known toplay a role in the 3 per second spike-and-wave discharges of absence seizures.AEDs that inhibit these T-calcium channels are particularly useful for controllingabsence seizures
  20. 20. enhancersGABA is produced bydecarboxylation of glutamatemediated by the enzymeglutamic acid decarboxylase(GAD). Some AEDs may actas modulators of thisenzyme, enhancing theproduction of GABA anddown-regulating glutamate(see the image below).Some AEDs function as anagonist to chlorideconductance, either byblocking the reuptake ofGABA (eg, tiagabine [TGB])or by inhibiting itsmetabolism as mediated byGABA transaminase (eg,vigabatrin [VGB]), resultingin increased accumulation ofGABA at the postsynapticreceptors.Gamma-aminobutyric acid (GABA)-A receptor mediates chloride (Cl-) influx,leading to hyperpolarization of cell and inhibition. Antiepileptic drugs mayact to enhance Cl- influx or decrease GABA metabolism.
  21. 21. GABA Receptor Agonists The benzodiazepines most commonly used for treatment of epilepsy are lorazepam, diazepam, clonazepam, and clobazam. The first 2 drugs are used mainly for emergency treatment of seizures because of their quick onset of action, availability in intravenous (IV) forms, and strong anticonvulsant effects. Their use for long-term treatment is limited because of the development of tolerance. The 2 barbiturates mostly commonly used in the treatment of epilepsy are phenobarbital (PHB) and primidone. They bind to a barbiturate- binding site of the benzodiazepine receptor to affect the duration of chloride channel opening. They have been used widely throughout the world. They are very potent anticonvulsants, but they have significant adverse effects that limit their use. With the development of new drugs, the barbiturates now are used as second-line drugs for the treatment of chronic seizures.
  22. 22. Glutamate blockers Glutamate receptors bind glutamate, an excitatory amino acid neurotransmitter. Upon binding glutamate, the receptors facilitate the flow of both sodium and calcium ions into the cell, while potassium ions flow out of the cell, resulting in excitation. The glutamate receptor has 5 potential binding sites, as follows: The alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) site The kainate site The N -methyl-D-aspartate (NMDA) site The glycine site The metabotropic site, which has 7 subunits (GluR 1-7)
  23. 23. GABA Transaminase Inhibitors Gamma-aminobutyric acid (GABA) is metabolized by transamination in the extracellular compartment by GABA-transaminase (GABA-T). Inhibition of this enzymatic process leads to an increase in the extracellular concentration of GABA. Vigabatrin (VGB) inhibits the enzyme GABA-T.
  24. 24. Objective 4Discuss the pathophysiology of febrile convulsions andepilepsy
  25. 25.  Febrile seizures occur in young children at a time in their development when the seizure threshold is low. This is a time when young children are susceptible to frequent childhood infections such as upper respiratory infection, otitis media, viral syndrome, and they respond with comparably higher temperatures. Animal studies suggest a possible role of endogenous pyrogens, such as interleukin 1beta, that, by increasing neuronal excitability, may link fever and seizure activity.[3]Preliminary studies in children appear to support the hypothesis that the cytokine network is activated and may have a role in the pathogenesis of febrile seizures, but the precise clinical and pathological significance of these observations is not yet clear.[4, 5] Febrile seizures are divided into 2 types: simple febrile seizures (which are generalized, last < 15 min and do not recur within 24 h) and complex febrile seizures (which are prolonged, recur more than once in 24 h, or are focal).[6]Complex febrile seizures may indicate a more serious disease process, such asmeningitis, abscess, or encephalitis. Viral illnesses are the predominant cause of febrile seizures. Recent literature documented the presence of human herpes simplex virus 6 (HHSV-6) as the etiologic agent in roseola in about 20% of a group of patients presenting with their first febrile seizures. Shigella gastroenteritis also has been associated with febrile seizures. One study suggests a relationship between recurrent febrile seizures and influenza A. [7, 8] Febrile seizures tend to occur in families. In a child with febrile seizure, the risk of febrile seizure is 10% for the sibling and almost 50% for the sibling if a parent has febrile seizures as well. Although clear evidence exists for a genetic basis of febrile seizures, the mode of inheritance is unclear. [9] While polygenic inheritance is likely, a small number of families are identified with an autosomal dominant pattern of inheritance of febrile seizures, leading to the description of a "febrile seizure susceptibility trait" with an autosomal dominant pattern of inheritance with reduced penetrance. Although the exact molecular mechanisms of febrile seizures are yet to be understood, underlying mutations have been found in genes encoding the sodium channel and the gamma amino-butyric acid A receptor.
  26. 26. Objective 5Describe the role and synthesis of GABA in the brain
  27. 27. GABA-A GABA-A receptors are coupled to chloride channels activation of GABA receptors will permit chloride to diffuse into the cell, hyperpolarize the membrane and decrease the excitability of the cell.
  28. 28. GABA-B The GABA-B receptor is coupled to potassium channels, forming a current that has a relatively long duration of action compared with the chloride current evoked by activation of the GABA-A receptor. inhibit membrane excitability by opening K+ channels and inhibiting Ca++ channels.
  29. 29. Role of GABA GABA is made in brain cells from glutamate, and functions as an inhibitory neurotransmitter – meaning that it blocks nerve impulses. Glutamate acts as an excitatory neurotransmitter and when bound to adjacent cells encourages them to ―fire‖ and send a nerve impulse. GABA does the opposite and tells the adjoining cells not to ―fire‖, not to send an impulse.
  30. 30. Synthesis of GABA

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