Brain development

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  • Rate increases exponentially through the first half of gestation and continues into the second and third year postnatally
  • Teratogenic agent- irradiation, maternal alcoholism or cocaine abuse, maternal phenylalaninemia RUBELLA-best candidate to produce micrencephaly
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  • 1. BRAINDEVELOPMENT Kathryn Baltazar-Braganza, MD Fellow, Neurodevelopmental Pediatrics Philippine Children’s Medical Center
  • 2. MAJOR DEVELOPMENTAL EVENTS Major development event Peak occurrenceDorsal induction 3rd – 4th wk prenatalVentral induction 5th – 6th wk prenatalNeuronal proliferation and programmed 2nd -4th mo prenatalcell deathNeuronal migration 3rd – 5th mo prenatalNeuronal differentiation and organization Synaptogenesis 6th mo – 3 yr Initial pruning 3 – 5 yr Secondary reorganization AdolescenceMyelination 6th mo – 3 yr … 30 yr
  • 3. DISTURBANCES OF BRAIN DEVELOPMENT• Primary malformation – perturbation of developmental events resulting in failure of an anatomical structure to be formed• Secondary malformation – breakdown of previously formed structure as a result of a destructive event
  • 4. EMBRYONIC BRAIN DEVELOPMENT• The flat trilaminar disc is transformed to nearly cylindrical embryo• By the end of this period, the major organ systems has been established
  • 5. Dorsal Induction (Third to Fourth Week of Gestation)• Neurulation –the primordial nervous system begins to form along the dorsal aspect of the embryo DAY 18
  • 6. 24 days26 days
  • 7. Central Nervous System Segmentation •The most important stage in the early transformation of the developing brain Day 25 Three primary embryonic brain vesicles
  • 8. Day 32
  • 9. Ventral Induction (Fifth to Sixth Week of Gestation)•The prechordal mesoderm interacts with thedeveloping forebrain to initiate cleavage•Cleavage (horizontal plane): paired opticvesicles, olfactory bulbs and tracts•Cleavage(transverse plane)telencephalon,diencephalon•Cleavage (sagittal plane): paired cerebralvesicles, basal ganglia and lateral ventricles
  • 10. Neurodevelopmental Disorders of Induction and Segmentation• ETIOLOGY2.Multifactorial inheritance3.Single mutant genes4.Chromosomal abnormalities5.Certain rare syndromes6.Specific teratogen (aminopterin, thalidomide, valproic acid, carbamazepine)7.Specific phenotypes of unknown causes
  • 11. Maternal Risk Factors• Previous affected pregnancy• Inadequate intake of folic acid• Pregestational diabetes• Intake of valproic acid and carbamazepine• Low vitamin B12• Obesity• Hyperthermia
  • 12. Neurodevelopmental Disorders of Induction and SegmentationTwo Most Common Errors of Dorsal Induction2.Anencephaly- Failure of the anterior portion to close by 24 days’ gestation
  • 13. 2. Encephalocele• More restricted disorder resulting from failure of the anterior portion of the neural tube to close by 26 days• More common in the occipital region and less often in the frontal region
  • 14. Disturbances of the Ventral Induction• Impairments in the interaction between the prechordal mesoderm, the face and the developing prosencephalic vesicle
  • 15. Holoprosencephalies• Failure of one or more of the cleavage planes to develop within the prosencephalon by the 6th week of gestation• Severe midline dysgenesis and failure to form distinct telencephalic, diencephalic and olfactory structures• Cognitive and motor development research/neuroimaging.htm is usually profoundly impaired
  • 16. Midline Prosencephalic Dysgenesis1. Septo-optic dysplasia2. Agenesis of the corpus callosum3. Agenesis of the septum pellucidum• Dysgenic alteration within the midline structure of the prosencephalon
  • 17. Schizencephaly• Primordial cells destined to become part of the cortex fail to form• Complete agenesis of a part of the cerebral wall, resulting in a thickened cortical mantle with deep seams or clefts
  • 20. NEURONAL PROLIFERATION• EARLY PROLIFERATION (Second Month of Gestation)- Single layer of pseudostratified columnar epithelium ventricular cells 100% of ventricular cells are actively proliferating
  • 21. NEURONAL PROLIFERATION• LATER PROLIFERATION (Second to Fourth Month of Gestation)- Peak period of neuronal proliferation- Increases exponentially through the first half of gestation into the second and third year postnatally- 2 distinct phases of proliferative activity
  • 22. 2 distinct phases of proliferative activity1. 10-20 weeks• major period of neuroblast production• most pyramidal neurons are generated2. 4-5 months postnatally• associated with glial agenesis
  • 23. Fundamental Embryonic Zones
  • 24. Neurodevelopmental DisordersMICRENCEPHALY – heterogeneous group of disorders characterized by reduced brain size and weight
  • 25. Primary Micrencephaly or Micrencephaly Vera• Genetic chromosome abnormalities, MCA/MR syndromes, maternal toxic-metabolic disorders or intrauterine exposure to a known CNS teratogen• Decreased neuronal proliferation or increased cell death during the peak period of neurogenesis• Genetic: cell cycle control and mitotic spindle organization
  • 26. Isolated Micrencephaly• Neurological deficits may not be present during infancy• Nonfocal minor motor impairment are common• Considerable variation in the level of cognitive function
  • 27. MEGALENCEPHALY• Increased brain size and weight• Genetic, chromosomal, endocrine and overgrowth syndromes• SEVERE CASES: Intellectual disabilities, motor impairment and seizures maybe present
  • 28. NEURONAL MIGRATION• Mass movement of neurons from the germinal zone to their ultimate destination• Peak Period: 3rd – 5th month of gestation• Radially(straight-out), tangentially (across- then-out) or diagonally (across-and-out)
  • 29. The Subplate• Early generated neuroblast will differentiate as they migrate through the IZ and come to reside in the SP• Morphological maturation neuropeptides, neurotrophins and GABA• Orchestrate the directionality and positioning of ingrowing afferent fibers
  • 30. The Cortical Plate• 7th – 10th week• Neurons acquire full complement by the end of the 5th month• Two predominant waves: 1. 8-10 weeks 2. 11-15 weeks
  • 31. Cellular Mechanism• Neurons migrate by an ameboid mechanism where the neuron is propelled forward in a RADIAL direction• Radial-glial fibers provide guidewire that establishes a direct radial trajectory to the outermost layer of the cortical plate
  • 32. Cellular Mechanism• Cell-cell interactions: selective binding affinities exhibited by migrating neuron for glial fibers as well as extracellular matrix• Interneurons appear to use the corticofugal axonal system as a scaffold for their migration into the cortex
  • 33. Formation of Gyri and Sulci• Fifth month of gestation• Primary and secondary convolutions: predictably relative to specific cortical cytoarchitectonic fields• Tertiary convolutions: develop during the final months of gestation
  • 34. Neurodevelopmental Disorders: NEURONAL MIGRATION DISORDERS• Result from either focal or generalized disruption• Primary disturbances- anomalous formation of the cortical plate and cortical laminae• Salient feature: aberration in the normal pattern of gyri and sulci
  • 35. Early (2-4 months gestation)• Severe, often diffuse defects• Causally related to specific genetic and chromosomal disorders, MCA/ MR syndromes or teratogenic agents Mechanisms of Development 105 (2001) 47±56
  • 36. Agyria (Lissencephaly) • Onset probably no later than the 3rd month of gestation • near or complete absence of secondary and tertiary gyriScienceDaily (Mar. 22, 2009)
  • 37. Pachygyria • Onset no later than the fourth month of gestation • Relatively few, unusually broad gyri and few sulciNeuroradiology, Radiology, Anatomy, MRI and CT Cases - for Medical Professionals
  • 38. Microgyria• Onset no later than the 4th or 5th mo• Cortex has increased number of very small gyri and absent or shallow sulci• Molecular layers of adjacent gyri are fused together J Med Genet 2005;42:369-378
  • 39. Early NMDs• Neurodevelopmental outcome: hypoactivity, hypotonia, motor dysfunction, intellectual disabilities (often severe) and seizure
  • 40. Late (5-6 months gestation)• Result in less severe or focal defects• Some neurons survive and appear capable of forming limited numbers of connections
  • 41. Neuronal Heterotopias• Clusters of ectopically positioned neurons that may be distributed anywhere along the migratory trajectory• Detection using MRI are often difficult• Associated with intractable partial epilepsy and infantile spasms
  • 42. Verrucose Dysplasia or Brain Warts• Tiny herniations of neurons from layer II that protrude into layer I and spill over onto the cortical surface• Appear as round, flat disks of tissue poised atop the gyrus• Associated with developmental language disability• Up to 26% of brains from neurologically normal individuals
  • 43. NEURONAL DIFFERENTIATION AND ORGANIZATION• Process by which newly migrated sheet of neurons express their distinctive morphological and biochemical phenotype (DIFFERENTIATION) and arrange themselves into large-scale networks of functional circuits (ORGANIZATION)• Begins around 6 months and extends through the 2nd and 3rd years of postnatal life
  • 44. Axonal and Dendritic OutgrowthAXONAL COMPARTMENT- contains a variety of membranousorganelles: mitochondria, lysosomal bodies, synaptic vesiclesand axosplasmic reticulum•Lack the capability for local protein synthesis: axoplasmictransport•Axons elongate by continuously incorporating newlysynthesized neurofilaments and microtubules in advancinggrowth cone
  • 45. Axonal and Dendritic Outgrowth• DENDRITIC COMPARTMENT: rich in ribosomes• Dendritic spines- represent the major postsynaptic targets of excitatory synaptic input that are critical for normal coding, storage and retrieval of information
  • 46. • Many forms of mental retardation and cognitive disability are associated with abnormalities in dendritic spine morphology• spine morphology is altered in response to certain forms of LTP-inducing stimulation Spine architecture and synaptic plasticity Review Article Trends in Neurosciences, Volume 28, Issue 4, April 2005, Pages 182-187 Holly J. Carlisle, Mary B. Kennedy
  • 47. Axonal Pathfinding and Target Recognition • Consistency in the pathway that axons from the same cell group travel to reach their respective target field • Chemotrophic signals and components of the extracellular matrix: guidance cues within the microenvironment
  • 48. Dendritic Arborization and Spine Formation • Dendritic tree provides a major proportion of the membrane surface area utilized by individual neurons to integrate information • Dendritic spines: postsynaptic targets of corticocortical and cortical afferent fibers
  • 49. Dendritic Arborization and Spine Formation
  • 50. The Synapse• Composed of presynaptic and postsynaptic elements that allows neurons to rapidly communicate with one another using chemical signals
  • 51. Early Synaptogenesis• Found by 15 weeks gestation, immediately above the CP in the MZ and below CP within the SP• Subplate neurons: express rich variety of neuropeptides and neurotrophin receptors• SP: “waiting compartment” and “traffic cop” for afferent fibers
  • 52. Later Synaptogenesis• First 2 years of postnatal life constitute a period of rapid cortical expansion• Total synaptic number and density continues to increase dramatically until about 2 or 3 years of age• 5 years: cortical expansion has ceased and packing density continues to decrease
  • 53. Later Synaptogenesis• Synaptic reorganization and diminution in gray matter volume occur throughout adolescence and early adult years• Strategy of redundancy: ensure prompt and complete innervation of all available targets• Selective pruning could occur later
  • 54. Neurodevelopmental Disorders• Aberrant cortical microcircuitry that alters the integrity of electrochemical signaling• Disorders maybe genetic, chromosomal and toxic-metabolic disturbances• Intellectual disability – impaired dendritic arborization and dendritic spine dysgenesis
  • 55. Neurodevelopmental Disorders• Intellectual disability• Rett syndrome• Infantile Autism• Down Syndrome• Fragile X Syndrome• Angelman Syndrome• Duchenne Muscular Dystrophy
  • 56. Synaptic Neurochemistry• Appearance of specialized biochemical pathways occurs after migration is completed• Cathecolamines, monoamines, Ach and amino acid neurotransmitters: within nerve terminal• Neuroactive peptides: neuronal cytoplasm
  • 57. Afferent System - NOREPINEPHRINE• Nucleus locus coeruleus in the rostral portion of the pons• Most dense- primary motor and sensory cortices, sparsest-temporal cortex, intermediate – occipital cortex• Enhances selectivity and vigor of cortical response to incoming sensory stimuli from the thalamus
  • 58. Afferent System - SEROTONIN• Dorsal and median raphe nucleus in the midbrain and rostral brain stem• Provide a very diffuse innervation to the cerebral cortex and limbic system• Modulation of internal behavioral states
  • 59. Afferent System - DOPAMINE• Ventral tegmental area of the midbrain• Innervate the limbic system and the frontal cortex• Frontal lobe functions: motivation, drive, motor function and mood-aggression and memory-attentional mechanisms
  • 60. Afferent System - ACETYLCHOLINE• Basal forebrain complex- base of the midbrain and telencephalon• Innervates cortex, hippocampus and the limbic system• Memory, attention and vigilance
  • 61. Intrinsic System - GABA• Primary inhibitory neurotransmitter• Widely distributed throughout all cortical layers-laminae II and IV• Cortical excitability and local information processing- neurodevelopmental and psychiatric disorders• Cognition, anxiety and seizure
  • 62. Intrinsic System- NEUROPEPTIDES• Hypothalamic-releasing hormones, neurohypophyseal hormones and pituitary hormones• Somatostatin, vasoactive intestinal polypeptide, cholecystokinin and neuropeptide Y-found in each of the cortical layers
  • 63. Efferent System- GLUTAMATE AND ASPARTATE• Most neurons are capable of excitation w/glutamate• Glutamate : pyramidal neurons which constitute the primary output neurons from the cortex• Used extensively by the commissural and association fibers of the hippocampus• Optimal amount is necessary to mediate critical events in development
  • 64. Neurodevelopmental Disorders Disorder Transmitter interactionAutism Serotonin and glutamate AcetylcholineADHD Dopamine and Noradrenaline Glutamate and DopamineLesch-Nyhan DopamineSyndromeOCD Glutamate, serotonine and Ach Serotonine anddopamineTourette syndrome Dopamine, noradrenalineIdiopathic epilepsies Glutamate and GABA
  • 65. Myelination (6th mo AOG to Adulthood) • Myelin membrane: lipid bilayer sandwiched between monolayers of protein • Oligodendroglial cells- originate within the VZ and SVZ of the embryonic neural tube • Glial proliferation- peaks during early 2 years
  • 66. Cellular Interaction During Myelination
  • 67. Myelination in the Cerebral Cortex1. Proximal pathways myelinate before distal pathways2. Sensory pathways myelinate before motor pathways3. Projection pathways myelinate before association fibers
  • 68. Myelination in the Cerebral Cortex J Neuropathol Exp Neurol. 1988 May;47(3):217-34. Sequence of central nervous system myelination in human infancy. II. Patterns of myelination in autopsied infants. Kinney HC, Brody BA, Kloman AS, Gilles FH.•
  • 69. Neurodevelopmental DisordersPRIMARY DISTURBANCES- deficient myelin production is the most salient pathological finding• Cerebral White Matter Hypoplasia• Prematurity• Amino and Organic Acidopathies• Hypothyroidism• Undernutrition• Deletion 18q syndrome
  • 70. Neurodevelopmental DisordersPOTENTIAL DISTURBANCES• Perinatal/ Early Infantile Insults• Iron DeficiencyASSOCIATED DISTURBANCE• Congenital Rubella• Rubinstein-Taybi Syndrome• Down Syndrome
  • 71. DOES BRAIN DEVELOPMENT END HERE?Complex scaffolding of three categories of neural processes:3.gene-driven4.experience-expectant5.experience-dependent
  • 72. Experience-expectant• “sensitive periods”• developmentally timed periods of neural plasticity for which certain types of predictable experience are expected to be present
  • 73. Experience-expectant• process of overproduction and selective elimination of synapses brain is made ready to capture critical and highly reliable information from the environment
  • 74. Experience-dependent• development involves the brain’s adaptation to information that is unique to an individual• does not occur within strictly defined critical periods• learning and memory: encoding information that has adaptive value to an individual but is unpredictable in its timing or nature
  • 76. EVIDENCE FOR HUMAN NEURAL PLASTICITY• Language development• Children rapidly acquire an enormous amount of vocabulary, grammar, and related information.• For middle-income American families, the rate of vocabulary acquisition is directly related to the amount of verbal stimulation that the mother provides.