Brain Development I

Principles of Neural Development

Steps of Development and Placement of Neurons

Proliferation (cell generation by mitosis) occurs inside neural tube. Neurogenesis term used to describe nerve cell production
Mitotic cycle of each cell follows a fixed sequence, resulting in production of neuroblasts (nerve cell precursors) or glioblasts (glial cell precursors)
Migration – after proliferative phase (but not before 6 wks gestation), neuroblasts move to permanent location. The migration process is as follows:
- Early neural tube consists of ventricular zone of mitotic cells and marginal zone of cellular processes
- Intermediate zone forms with cell proliferation
- By 8-10 weeks after conception, intermediate zone enlarges to form cortical plate
- Initial formation of cortical plate occurs by migration of cells to sixth layer of cortex and subsequent migrations follow an inside-out pattern (thus, top layer is formed last by neurons that must migrate past cells of the deeper layers)
- Second migratory wave is at 11-15 weeks gestation
- Cells migrate in sheets called laminae
- Migration occurs by guidance by radial fibers
- Radially oriented glia – group of glial cells radially oriented from ventricular to basal surface and guides migration of neurons
- Migration in cerebellum occurs in outside-in pattern- b/w 9-13 wks gestation, neuroblasts migrate to outermost layer of cerebellum and proliferate. Bergmann glia responsible for migration
- By 18 weeks gestation, all cortical neurons have reached designated location
- Migratory defects include complete failure of migration; curtailment of migratory cells along migratory pathway; aberrant placement of postmitotic neurons within target structure (ectopia)
Aggregation – during migratory cycles, neurons selectively aggregate to form cellular masses, or layers. This is called lamination. Two events in aggregation process
- neurons come together and establish adhesion between necessary cells
- align themselves with respect to immediate neighbors
Cytodifferentiation (cellular differentiation) – four major concurrent aspects
- Development of cell body
- Selective cell death: 40-75% of all neurons die during development; only a limited number of neurons succeed in sending axons to correct targets
- Axonal and dendritic development
  - As migrating neuronal cells reach designated position, dendrites begin to sprout (arborization).
  - Extensions (spines) begin to extend from dendrites
  - Dendritic growth begins prenatally and proceeds slowly
  - Majority of arborization and spine growth occurs postnatally, with most intensive period occurring birth to 18 months
  - Development highly sensitive to environmental stimulation
  - Chemospecificity – biochemical specificity programmed into each nerve cell determining that contacts between cells are made. As neuron forms axon and dendrites, sends out advance spray of cellular processes (microfilaments) that seek chemical attraction, forming appropriate connections with nerve cells.
- Synaptogenesis – termination of axonal growth, selection of synaptic sites, and formation of synapse; regional increases in synaptic density accompany the emergence of function:
  - Visual cortex – dendritic and synaptic growth stops at age 8 months, but process of synapse elimination continues to 3 years of age
  - Frontal cortex – dendritic and synaptic density reach peak in infancy and early childhood and decline b/w 2 and 16 yrs
- Pruning – neurons overproduced and many initial connections are random; subsequent development eliminates (prunes) neurons.
  - Process often begins at dendritic spines
  - Purposeful sculpting of brain; eliminates weakly reinforced or redundant connections
  - Promotes neural efficiency
  - Primarily a postnatal process, eliminating 40% of cortical neurons during childhood
  - Proceeds at different times and rates. Ex- pruning of visual cortex begins at 1 and complete by 12 yrs; pruning of prefrontal from 5-16 yrs

Glial Cell Development and Myelogenetic Cycles

Glial cells include:

astrocytes
oligodendrocytes
microglia
Functions – respond to injury; regulate neuronal metabolism, contributing to BBB; through myelination, play role in electrical activity
Glial cells are relatively immature in early stages of CNS development (no gliosis to penetrating wound in newborn brain)
Most important role is myelination
Myelination starts in spinal cord, spreads to medulla, pons, midbrain, finally to diencephalon and telencephalon
Cortical regions myelination begins posterior and moves anterior, with parietal and frontal lobes last
Frontal and parietal myelination begins after birth and continues to adolescence and adulthood
Increase in brain weight postnatally primarily myelination
Myelination of regions correlates with emergence of function

Myelogenesis – development of myelin

Primordial (“premature”) fields myelinate before birth – somesthetic cortex, primary visual cortex, primary auditory cortex
Intermediate (“postmature”) fields myelinate during first 3 postnatal months – secondary association areas
Terminal fields myelinate between fourth postnatal month and 14 yrs of age – classical association areas

Metabolic and Biochemical Agents

Nucleic acids – DNA, RNA

brain content high during early phases of development, then gradually decreases
DNA content reliable predictor of cell number
Two periods of cell proliferation detected by measuring DNA: 15-20 wks gestation is neuroblast proliferation; 25 wks gestation to 2 yrs age glial cell multiplication
Lesch-Nyhan syndrome – mutation of gene affects enzyme involved in making of nucleotide bases of nucleic acids

Amino acids

Absorption of amino acids from blood and rates of protein synthesis higher for newborns than adults
Inborn errors of amino acid metabolism – PKU

Lipid

In fetal brain, little difference found between lipids in gray and white matter
Adult pattern attained during myelination, which increase in three major lipids (cholesterol, cerebrosides, sphingomyelin)
Disorders of lipid metabolism – Tay-Sachs, Niemann-Pick

Neurotransmitters

acetylcholine, dopamine, glutamate, epinephrine, norepinephrine
increase in levels serve as developmental signals for neural tube formation, germinal cell proliferation, and neuronal and glial differentiation

Chronology of Gross Neural Development

In general, CNS, brain and spinal cord development is:

head (cephalic) to tail (caudal)
near (proximal) to far (distal)
inferior (subcortical) to dorsal (cortical)

PRENATAL DEVELOPMENT

Development of neural tube:

18 days – CNS and PNS develop from midline ectoderm layer of fertilized egg
Neural plate appears from dorsal ectoderm
In the center of the plate, the cells on edge become narrower on inner surface, while those surrounding become narrower on outer surface, forming neural groove formed of neural folds.
This gradually deepens, and folds over onto itself. It starts to close starting at midpoint and extending in both rostral and caudal directions.
As it closes, there are two open ends (neuropores), which close at 25 days gestation, forming neural tube
Anterior end gives rise to brain, posterior end forms spinal cord
Process of conversion from open groove to sealed tube is neurulation
Neural tube defects occur third to four weeks gestation: neural tube has difficulty closing (anterior- anencephaly; caudal- spina bifida)

Neural crest cells are adjacent to neural tube. They are free of overlying ectoderm and form irregular bundle of tissue surrounding tube. These clumps of cells migrate and differentiate to form ganglia

Regional Development

Three vesicles develop at anterior end of neural tube

prosencephalic (becomes forebrain)
mesencephalic (becomes midbrain)
rhombencephalic (becomes hindbrain)

5th week gestation

prosencephalic vesicle divides into telencephalon and diencephalon rhombencephalic vesicle divides into metencephalon and mylencephalon

7th week of gestation

telencephalon transformed into cerebral hemispheres diencephalon into thalamus and related structures metencephalon into cerebellum and pons myelencephalon into medulla oblongata

In vestigial form, the neural tube becomes the cerebral ventricles and cerebral aqueduct
Caudal (tail end) becomes spinal cord, elongating and developing into segments, each of which is associated with sensory and motor innervation
Spinal cord keeps remnant of neural tube as central canal
In cord, neural tissue desegregates into two main bodies of neurons – dorsal (posterior) horns and ventral (anterior) horns, divided by sulcus limitans
Dorsal horns, also called alar plate, receive axons from dorsal root ganglia and involved in sensory events
Ventral horns, also called basal plate, contain cell bodies of axons that innervate muscles and considered part of motor system

Development of Cortex

Corticogenesis begins 6th week gestation
6th week gestation – basal ganglia visible
8-10 weeks gestation – early cortical plate forms from migrating cells; four layers of cortex are visible (ventricular, subventricular, intermediate, and marginal)
As cortex develops, first expands anteriorly to form frontal lobes, then dorsally to form parietal lobes, then posteriorly and inferiorly to form temporal and occipital lobes
Posterior and inferior expansion pushes cortex into a C shape, which shapes many of the underlying structures (lat vents, head of caudate of BG, hippocampus)
5th month gestation – increasing number of cortical cells causes smooth surface of brain to develop pattern of convolutions and sulci
Pattern of convolutions and sulci – primary, then secondary, then tertiary
- hippocampal sulcus: 13-15 wks
- parieto-occipital, calcarine, olfactory bulb sulci: 19 wks
- sylvan (lateral) and rolandic (central) sulci: Spreen says 24 wks; other article says 14 wks
- secondary sulci (first temporal sulcus, superior frontal sulci): 28 wks
- tertiary not formed until third trimester and continue development after birth
Gyral pattern of adult present at birth
Gyri and sulci patterns form after neuronal migration and reflect processes of neuronal specialization, dendritic arborization, synaptic formation, and pruning
Formation of gyri signals that intracortical connections are established
Extreme alterations suggest deviations in cortical connections and potential deficits: polymicrogyria – small, densely packed gyri associated with LD, MR, and epilepsy
6th month gestation – cortical plate thickens due to migrating neurons and more layers are formed, giving cortex final six-layered composition

Development of Intercerebral Commissures

Growth is slow and related to maturation of association cortex
First commissural fibers cross in rostral end of forebrain at 50 days gestation, creating anterior commissure and hippocampal commissure
Fibers of CC cross develop in parallel with various cerebral lobes and process not complete until after birth
Failure results in agenesis of CC

Development of Ventricles

Cavities within cerebral vesicles of neural tube form vents and central canal of spinal cord
Cavities of cerebral vesicles differentiate into
- two lateral vents
- aqueduct of Sylvius
- fourth vent

POSTNATAL DEVELOPMENT

Brain weighs b/w 300-350 g and grows rapidly, reaching 80% of adult weight at 4 yrs.
Cortical surface area of hemispheres doubles, reaching adult dimensions by age 2
Increase in brain size inferred from head circumference
Growth of brain due to increase in size, complexity, and myelination (rather than number) of nerve cells
Primary sensory and motor areas are most advanced, followed by progressive development of adjacent sensory association areas, and finally parietal and temporal association areas.
Prefrontal lobes least developed at birth, not much development until after second year
Functional organization of nervous system reflecting increased responsiveness to environmental stim
Functional elaboration of association fibers and tracts; increasing connectivity
EEG changes – after birth irregular and low amplitude; by 4 months of age, first slow rhythm (3-4 discharges per second) becomes evident, primarily over occipital cortex; frequency of EEG discharge increases over tie until characteristic stable alpha rhythms (11-12 per second) is attained

Maturation of the Cortex in Early Postnatal Period

Neurogenesis begins at front edge of cortex where frontal cortex abuts inferotemporal cortex and proceeds back to primary visual cortex
Primary sensory nuclei in thalamus, including ventrobasal complex (somatosensory), medial geniculate body (auditory), and lateral geniculate body (visual) generated first and establish axonal connections to cortex first.
Nuclei that innervate frontal, parietal, and inferotemporal cortex are last

PRENATAL THROUGH POSTNATAL PROCESSES

Myelination

Sensory areas myelinate before motor (may be responsible for comprehension/ production language disparity)
Myelination of callosal and associational cortical regions may continue into third and fourth decade of life

Synaptogenesis

Synaptogenesis and synapse elimination co-occur over most of early postnatal development
Primary mode of learning in nervous system takes place when juncture is formed or modified as a function of experience
Synaptic connectivity is considered the primary means by which knowledge is represented in the brain
Generation of synapses in isocortex accelerates around birth; simultaneous peaking of synaptogenesis across all cortical areas
Brain suddenly starts to generate massive numbers of synapses just before environmental experience (ie, birth) in all regions associated with sensory, motor, motivational, and linguistic ability
Synapse generation overshoots by a substantial proportion in first six months, then declines to adult values
Five stages of synaptogenesis
- Synapses present in preplate
- Synapses generated in cortical plate
- Synaptogenesis synchronized in global perinatal “burst”
- Stabilized high level lasting from late infancy until puberty
- Synapses steadily decline in density and number from puberty through adulthood

Timing of Events – A Summary

First Trimester

Development of neural tube
Every neuron in nervous system generated in first trimester, with exception of tail of distribution of last layer of isocortex and external granular layer of cerebellum (hippocampal dentate gyrus and olfactory bulb neurons are generated throughout life
Basic axonal pathways of brainstem laid down
Migration of cells
Differentiation of cells

Second Trimester

Basic wiring of brain (large patterns of connectivity between neural regions)
Connection of thalamus to all regions of isocortex- pattern of connections resembles adult pattern
Intracortical pathways begin to be established
Appearance of CC around 90 day gestation
Apoptotic neuronal death (“apoptotic” suggests that it is organized cell death, not disorganized dissolution of the cell)
Activity-dependent self-organization of the nervous system- first motor activity of fetus begins

Third Trimester

Reciprocal connectivity from higher-order cortical areas to primary areas
Initial myelination
Large descending pathways from cortex- “top down” connectivity with sensory and motor systems
Synaptic connections between isocortex and related structures

By Birth

all cells are generated
all major incoming sensory pathways are in place and have gone through period of refinement of total cells, connections, and topographic organization
intracortical and connectional pathways well developed (output pathways lag)
microstructure of features such as motion and orientation in visual system present
“Big” cortical regions (primary sensory and motor) have adult input and topography

Evidence that Social Environment Influences Brain Development

Environmental deprivation and/or stress

Environmental deprivation and/or stress can alter neuronal, hormonal, and immune systems. The alterations may impair normal development (or impair recovery from brain trauma) in a transient or long-term way. Environmental enrichment may increase neuronal complexity, improve brain function, and facilitate recovery from brain injury.

Cortisol reactivity to stress, hippocampus and immune changes (McEwen, Gunnar)
PET scan and behavior changes in Romanian orphans (Carlson & Earls)
EEG differences related to cognitive development (Nelson, Thatcher, Fischer)
EEG differences related to emotional traits and caregiver responsivity (Dawson, Davidson, Fox, Calkins, Bell)
EEG differences related to medical status and caregiver responsivity (Als, Gilkerson)
Medical and behavioral development of preemies related to touch/massage (Field)
Dendritic complexity of rats in enriched environments (Diamond, Greenough)
Social behavior and brain changes in socially isolated monkeys (Harlow; Suomi)
Speculation about possible effects of child abuse and neglect (Perry; Teicher; Schore)

Sensitive Periods

Environmental influences on specific abilities are more pronounced during sensitive periods

Axon growth and synapse formation in visual processing areas of kittens exposed to postnatal visual experience (Hubel & Wiesel)
Brain growth and behavior of deafened songbirds (Marler)
EEG changes in prelingually and postlingually deafened adults, in brain areas that react to visual vs. auditory inputs, and response to grammatical vs. content words (Neville)
Age differences in phoneme detection and language-learning (Kuhl, Stromswold)
Age differences in recovery from brain damage involve age at injury, age at testing, and type of test administered, sensitive and “insensitive periods occur (Kolb)

Individual Differences

Some individual brain-behavior differences may be relatively subtle

EEG activation patterns may be associated with emotional intensity and valence which are seen as temperament differences (Dawson, Davidson, Fox, Nelson)
Stability of early phonological awareness, vocabulary, and later reading and math abilities (Molfese, Hart, & Risley; Morrison; Fletcher & Shaywirtz) despite transitory impact of specific expressive language disorders (Whitehurst; Rapin)

Phenotypic Variation

Children with a particular brain disorder rarely show a specific, unique pattern of behavior. Effects of brain disorders vary with nature of the brain insult, environmental support and stress; sex and handedness; age at time of injury; age at time of outcome measurement; and nature of the outcome measures (Fletcher, Yeates, Taylor, Dennis, Shapiro, Satz, Baron, etc., etc.)

Some points regarding intervention

Enrichment/deprivation powerful at all ages, though deprivation may be particularly deleterious during initial development of key abilities
Critical to NOT deprive of visual, auditory, and tactile stimulation, language input, and responsive “stress buffering” care providers during infancy
Phonological awareness and vocabulary at kindergarten predict long-term school success
Children may be maximally attuned to sounds of own language between birth and five; decreased skills for learning speech sounds after that
Early accurate diagnosis better than a “wait-and-see” approach
Younger age at acquired injury (after first few months of life) associated with more severe cognitive and behavioral impairments
Best intervention is PREVENTION – vast majority of brain damage is preventable via social/environmental factors (especially injuries). FYI, best prevention involves training in supervisory practices and environmental modifications, NOT safety education programs.