BRAIN DEVELOPMENT

Kathryn Baltazar-Braganza, MD

Fellow, Neurodevelopmental Pediatrics

Philippine Children’s Medical Center

MAJOR DEVELOPMENTAL EVENTS

Major development event Peak occurrence

Dorsal induction 3rd – 4th wk prenatal

Ventral induction 5th – 6th wk prenatal

Neuronal proliferation and programmed cell death

2nd -4th mo prenatal

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

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

• The flat trilaminar disc is transformed to nearly cylindrical embryo

• By the end of this period, the major organ systems has been established

EMBRYONIC BRAIN DEVELOPMENT

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

24 days

26 days

Central Nervous System Segmentation

•The most important stage in the early transformation of the developing brain

Day 25Three primary

embryonic brain vesicles

Day 32

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

• ETIOLOGY

1.Multifactorial inheritance

2.Single mutant genes

3.Chromosomal abnormalities

4.Certain rare syndromes

5.Specific teratogen (aminopterin, thalidomide, valproic acid, carbamazepine)

6.Specific phenotypes of unknown causes

Neurodevelopmental Disorders of Induction and Segmentation

Maternal Risk Factors

• Previous affected pregnancy

• Inadequate intake of folic acid

• Pregestational diabetes

• Intake of valproic acid and carbamazepine

• Low vitamin B12

• Obesity

• Hyperthermia

Two Most Common Errors of Dorsal Induction

1.Anencephaly

- Failure of the anterior portion to close by 24 days’ gestation

Neurodevelopmental Disorders of Induction and Segmentation

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

Disturbances of the Ventral Induction

• Impairments in the interaction between the prechordal mesoderm, the face and the developing prosencephalic vesicle

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 is usually profoundly impaired

http://hpe.stanford.edu/research/neuroimaging.html

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

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

ENCEPHALIZATION & FORMATION OF THE CEREBRAL CORTEX

NEURONAL PROLIFERATION

NEURONAL PROLIFERATION

• EARLY PROLIFERATION (Second Month of Gestation)

- Single layer of pseudostratified columnar epithelium ventricular cells

100% of ventricular cells

are actively proliferating

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

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

Fundamental Embryonic Zones

Neurodevelopmental Disorders

MICRENCEPHALY – heterogeneous group of disorders characterized by reduced brain size and weight

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

Isolated Micrencephaly

• Neurological deficits may not be present during infancy

• Nonfocal minor motor impairment are common

• Considerable variation in the level of cognitive function

MEGALENCEPHALY

• Increased brain size and weight

• Genetic, chromosomal, endocrine and overgrowth syndromes

• SEVERE CASES: Intellectual disabilities, motor impairment and seizures maybe present

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)

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

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

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

• 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

Cellular Mechanism

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

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

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

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)

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

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

Early NMDs

• Neurodevelopmental outcome:

hypoactivity, hypotonia, motor dysfunction, intellectual disabilities (often severe) and seizure

Late (5-6 months gestation)

• Result in less severe or focal defects

• Some neurons survive and appear capable of forming limited numbers of connections

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

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

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

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

• 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

Axonal and Dendritic Outgrowth

• 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 ArticleTrends in Neurosciences, Volume 28, Issue 4, April 2005, Pages 182-187

Holly J. Carlisle, Mary B. Kennedy

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

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

Dendritic Arborization and Spine Formation

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/

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

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

• 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

Later Synaptogenesis

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

Neurodevelopmental Disorders

• Intellectual disability

• Rett syndrome

• Infantile Autism

• Down Syndrome

• Fragile X Syndrome

• Angelman Syndrome

• Duchenne Muscular Dystrophy

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

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

• 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

Afferent System - SEROTONIN

• 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

Afferent System - DOPAMINE

• Basal forebrain complex- base of the midbrain and telencephalon

• Innervates cortex, hippocampus and the limbic system

• Memory, attention and vigilance

Afferent System - ACETYLCHOLINE

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

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

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

Neurodevelopmental Disorders

Disorder Transmitter interaction

Autism Serotonin and glutamateAcetylcholine

ADHD Dopamine and NoradrenalineGlutamate and Dopamine

Lesch-Nyhan Syndrome

Dopamine

OCD Glutamate, serotonine and AchSerotonine anddopamine

Tourette syndrome Dopamine, noradrenaline

Idiopathic epilepsies Glutamate and GABA

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

Cellular Interaction During Myelination

http://www.mc.vanderbilt.edu/histology

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

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.

•

Myelination in the Cerebral Cortex

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

Neurodevelopmental Disorders

POTENTIAL DISTURBANCES

• Perinatal/ Early Infantile Insults

• Iron Deficiency

ASSOCIATED DISTURBANCE

• Congenital Rubella

• Rubinstein-Taybi Syndrome

• Down Syndrome

DOES BRAIN DEVELOPMENT END HERE?

Complex scaffolding of three categories of neural processes:

1.gene-driven

2.experience-expectant

3.experience-dependent

Experience-expectant

• “sensitive periods”

• developmentally timed periods of neural plasticity for which certain types of predictable experience are expected to be present

• process of overproduction and selective elimination of synapses brain is made ready to capture critical and highly reliable information from the environment

Experience-expectant

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

EVIDENCE FOR HUMAN NEURAL PLASTICITY

www.medicalook.com

• 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.

EVIDENCE FOR HUMAN NEURAL PLASTICITY

CLINICAL APPLICATIONS

EXPERIENCE