1. BRAIN
DEVELOPMENT
Kathryn Baltazar-Braganza, MD
Fellow, Neurodevelopmental Pediatrics
Philippine Children’s Medical Center

2. MAJOR DEVELOPMENTAL
EVENTS
Major development event Peak occurrence
Dorsal induction 3rd – 4th wk prenatal
Ventral induction 5th – 6th wk prenatal
Neuronal proliferation and programmed 2nd -4th mo prenatal
cell death
Neuronal migration 3rd – 5th mo prenatal
Neuronal differentiation and organization
Synaptogenesis 6th mo – 3 yr
Initial pruning 3 – 5 yr
Secondary reorganization Adolescence
Myelination 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 days
26 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 the
developing forebrain to initiate cleavage
•Cleavage (horizontal plane): paired optic
vesicles, olfactory bulbs and tracts
•Cleavage(transverse plane)telencephalon,
diencephalon
•Cleavage (sagittal plane): paired cerebral
vesicles, basal ganglia and lateral ventricles

10. Neurodevelopmental Disorders of
Induction and Segmentation
• ETIOLOGY
2.Multifactorial inheritance
3.Single mutant genes
4.Chromosomal abnormalities
5.Certain rare syndromes
6.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 Segmentation
Two Most Common Errors of Dorsal Induction
2.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 http://hpe.stanford.edu/
• Cognitive and motor development research/neuroimaging.htm
is usually profoundly impaired

16. Midline Prosencephalic Dysgenesis
1. Septo-optic dysplasia
2. Agenesis of the corpus callosum
3. 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
rad.usuhs.edu

18. ENCEPHALIZATION & FORMATION
OF THE CEREBRAL CORTEX

19. NEURONAL PROLIFERATION

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 activity
1. 10-20 weeks
• major period of neuroblast production
• most pyramidal neurons are generated
2. 4-5 months postnatally
• associated with glial agenesis

23. Fundamental Embryonic Zones

24. Neurodevelopmental Disorders
MICRENCEPHALY – 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 gyri
ScienceDaily (Mar. 22, 2009)

37. Pachygyria
• Onset no later than the fourth month of
gestation
• Relatively few, unusually broad gyri and
few sulci
Neuroradiology, 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 Outgrowth
AXONAL COMPARTMENT- contains a variety of membranous
organelles: mitochondria, lysosomal bodies, synaptic vesicles
and axosplasmic reticulum
•Lack the capability for local protein synthesis: axoplasmic
transport
•Axons elongate by continuously incorporating newly
synthesized neurofilaments and microtubules in advancing
growth 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
http://cognitivephilosophy.net/brain-research/neuroplasticity-in-brief/

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 interaction
Autism Serotonin and glutamate
Acetylcholine
ADHD Dopamine and Noradrenaline
Glutamate and Dopamine
Lesch-Nyhan Dopamine
Syndrome
OCD Glutamate, serotonine and Ach
Serotonine anddopamine
Tourette syndrome Dopamine, noradrenaline
Idiopathic 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
http://www.mc.vanderbilt.edu/histology

67. Myelination in the Cerebral Cortex
1. Proximal pathways myelinate before
distal pathways
2. Sensory pathways myelinate before
motor pathways
3. 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 Disorders
PRIMARY 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 Disorders
POTENTIAL DISTURBANCES
• Perinatal/ Early Infantile Insults
• Iron Deficiency
ASSOCIATED DISTURBANCE
• Congenital Rubella
• Rubinstein-Taybi Syndrome
• Down Syndrome

71. DOES BRAIN DEVELOPMENT
END HERE?
Complex scaffolding of three categories of
neural processes:
3.gene-driven
4.experience-expectant
5.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

75. EVIDENCE FOR HUMAN
NEURAL PLASTICITY
www.medicalook.com

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.

77. CLINICAL APPLICATIONS
EXPERIENCE