Neural Development & Developmental Disorder

Between 4 weeks and 9 months the brain undergoes rapid development

Development of the Brain

Stages of neuroanatomical development 1. Zygote stage: Begins upon fertilization of the ovum and ends with the formation of the embryonic disc at approximately 14 days after conception. Conception involves 2 sets of 22 chromosomes, and one set of sex chromosomes. Total of 23 pairs of chromosomes (XX= female, XY= male)

Egg and sperm each contribute a complete single set of chromosomes. This includes 22 chromosomes plus the 23 sex chromosome (X or Y) Mitosis proceeds normally from the first cell division

From Conception to 8-14 days

2. Embryonic Stage (2 weeks 8 weeks): Begins at the full formation of embryonic disc. Ectoderm: forms nervous system (brain), fingernails, hair, and skin. Changes: 1. Thickens in the middle (neural plate) 2. Groove starts to form (neural groove) 3. Groove closes to form tube (neural tube) a. At the top of canal is neural crest, forms PNS

Simplified View of Neural Plate Formation

Formation of the Neural Plate with the thickening of Ectoderm

Formation of the Brain, Spinal Cord and PNS (Neuroectoderm)

Neuroectoderm forms when foundation for the three main structures has been developed: 1. 3 swellings a. Hindbrain b. Midbrain c. Forebrain 2. Closed Neural Tube becomes spinal cord central canal and ventricles of the brain. Spina bifida Neural Tube Defect (NTD) spinal cord doesnt close, often linked to mental retardation **NTDs can be discovered in utero **

Ectoderm to Neuroectoderm: 20 days to 30 days

(note the formation of the spinal nerves at 30 days and the three swellings that make up the hindbrain, midbrain and forebrain)

3. Fetal Period: Eight weeks to Birth (38 weeks)

 Foundation for the entire CNS is set 6 stages of CNS development complete the prenatal process

(a) Mitosis and Neurogenesis

Mitosis (cell division) or Neurogenesis in the ventricular zone, One cell division can lead to a daughter cell, will divide again forming an immature neuron

(b) Migration

vz = ventricular zone

Migration: cells move from VZ to their destination; this migration is aided by glial cells, abnormal migration found in a number of disorders. Filopodia (next slides, also) assist in finding location after leaving radial glial cells. Abnormalities in migration have been found in the CNS of people with learning disabilities, schizophrenia and autism

Forebrain Development

Growth Cones & Filopodia

Photomicrograph of growth cone & filopodia

(c) Differentiation
The process which gives rise to specific neurons and glial cells

(d) Synaptogenesis
Neuronal maturation 1. Elongation of axons (w/growth cones) 2. Establish terminals 3. Elongation of dendrites 4. Expression of NT Neurotrophic factors stimulate cell growth, i.e. nerve growth, factor helps neuron to mature.

(e) Cell Death

Apoptosis active cell death during development

(f) Synaptic Rearrangement

Active Cell Death 40%-50% neuronal loss occurs during the first 2 years of life, and it occurs on a different scale in adolescence (hormone related, final pruning) 1. Essential because many cells are unconnected and useless 2. Dysfunction in apoptosis is seen in postmortem brains of children with autism (particularly problems in cerebellum, midbrain, & hippocampus); insufficient hooking up of neurons

Post-natal brain development

1. At birth the brain weighs 25% of the full adult brain 2. By the age of 6 it increases to 95% a. Increase is due to myelination, synaptic development, neuronal maturation, glial cell growth b. At birth the brain is myelinated through the thalamus c. Myelination is in part based on experience (the premature baby will have substantially more myelin than that of the full term baby)

Cellular Development of the Postnatal Brain

Cells of the Cerebral Cortex

Cells of the Cerebellum

Critical Periods: Rapid changes in a system of an organism, if interrupted will result in permanent & irreversible problems Prenatal Critical Periods: these involve structural abnormalities (see next slide, brown bars) Postnatal Critical Periods: this varies with the function.
Examples: Uncorrected strabismus permanently impairs depth perception. Binocular vision begins within weeks after birth and ceilings between 1 and 3 weeks of age. Linguistic features (e.g., bilateral neural communication between left and right hemispheres) develop between ages 1 and 2, suggesting a critical period for language. Interference prevents the full acquisition of adult linguistic features.

Brain Cells can Continue to Develop in Abnormal Ways

Early Childhood

Adulthood

Experience can Modify Brain Cell Connections

How experience affects development 1. Experience-expectant plastic changes: CNS changes that rely on experiences during critical periods for specific synapses to develop. The primary sensory cortices require sensory stimulation for normal development, otherwise long lasting impairments occur (e.g., strabismus and depth perception impairment). 2. Experience-dependent plastic changes: unique experiences that occur during critical periods that affect brain development (e.g., musical training affects the sensorimotor cortex for playing and primary auditory cortex for listening).

Normal Plasticity or Apoptosis causes rearrangement of cells

Neuronal Degeneration due to Necrosis (cell damage due to to injury)Note subsequent damage
to other neurons, across or transneural loss

Rearrangement following Necrosis: Collateral Sprouting

Normal Development
Overall Brain Development Between Birth and 21 years old.

Age

Temporal Lobes or Language Areas, Birth - 21

Ages 1-2 interhemispheric (myelin and neurons) connections increase Ages 2-12 marked dendritic arborization in speech areas, occurs in waves Ages13-17 may have a large environmental component (e.g. education, socialization) in addition to effects of puberty on brain development.

Age

Parietal Areas, Birth - 21

Birth to 3 years rapid growth as child interacts with world. Corresponds with visuospatial and visuosensorimotor skills.
Continued steady growth in waves, corresponding with changes in temporal lobe. Age

Limbic System for Emotions/Attachment, Birth - 21

Includes the hippocampus, which develops by 1year, but is not fully connected with other brain areas for stable episodic memories (autobiographical). This occurs beginning around age 4.
Age

Increase during adolescence reflects shift from family to peer and pair bonding.

Frontal Lobes for Behavioral Control, Birth - 21

This includes motor cortex in cephalocaudal (head before arms/truck before legs) and proximodistal (head/trunk/arms before hand/fingers; or gross motor before fine motor) by age 9.
Executive Functions (planning, shifting, inhibiting, emotional regulation) in prefrontal cortex. Judgment in social settings for Age ambiguous situations established by age 14.

Disorders of Development
Congenital Birth Defects Congenital Teratogenic Agents Trisomy Disorders Williams Syndrome Autism

Teratogens Agents that cause congenital malformations during critical periods, and subtle alterations in the brain during sensitive periods

Critical Period Defect: Cleft Palate

Irreversible congenital abnormality affecting a critical period (palate development) during the embryonic and early fetal stages May affect pituitary growth as the palate and anterior pituitary are derived from the same embryonic tissue.

Critical Period Defect: Anencephaly (absence of brain)

Failure for the brain to grow beyond the rhombencephalon. Neonate failed to survive.

Critical Period Defect: Schizencephaly

Developmental of the brain affected during the fetal period (i.e., growth of the forebrain). Cells either failed to migrate or ventricular region failed to close.

Teratogens
Agents that cause congenital malformations

Fetal Alcohol Syndrome

Features: Growth retardation, neurodevelopmental abnormalities (fine motor skills, LD, behavior disorders, and mental retardation in 50%). Facial dysmorphia during embryonic period (week 4-8), CNS problems during the fetal period (migration problems, smaller dendrites, few neurons in brain regions)

Genetic Conditions: Chromosomal Abnormalities

Trisomy 21 (Downs Syndrome) Trisomy of other chromosomes
Edwards Syndrome (Trisomy 18) Pataus Syndrome (Trisomy 13)

Trisomy 21: Downs Syndrome

Non-disjunction of the 21st Chromosome

Anatomical Dysmorphia & Risk (Increase with

Maternal Age)
Just 1%20% graphed here

How does Trisomy 21 happen? First, normal development In normal development mitosis proceeds normally from the first cell division

In Downs Syndrome, nondisjunction of the 21st chromosome can happen at the first cell division

Non-disjunction of the 21st chromosome cab occur after the first cell division resulting in a mosaic form of Downs Syndrome

Faulty distribution can occur in the egg or sperm when the mother or father is a carrier.

Trisomy 18 Edwards Syndrome

Some Features of Edwards Syndrome

Facial: microcephaly, low set malformed ears Skeletal: webbed neck, overlapping of fingers and fixed flexion of fingers CNS: severe mental retardation, neural tube defect, ocular abnormalities Respiratory: apnea Cardiovascular problems
Gastrointestinal and genitourinary problems Life Span: death by 12-24 months (very few reach adulthood) Incidence: 0.2/1000 births

Trisomy 13: Pataus Syndrome

Features: 0.1/1000 births Spina bifida & cleft palate CNS: underdevelopment of frontal lobe (fails to divide) and corpus callosum Profound Mental Retardation Extra fingers and toes, deaf Life Span: 82% die in the first month, 5-10% die in first year.

Williams Syndrome Partial Deletion of the 7th Chromosome

Features: 1 in 20,000 births Neurodevelopmental delays, cognitive deficits, LD, ADHD Overly friendly, social Extremely empathic Low muscle tone Extremely sensitive hearing

Normal Control

Williams Syndrome

Specific Brain Areas Affected:

Amygdala activates more for threatening scenes and very little for threatening faces. This accounts for absence of anxiety in interpersonal interactions (no fear, hence overfriendliness).

Amygdala

Additional CNS Features in Williams Syndrome

Normal frontal & temporal lobes Reduction in parietal and occipital lobes Decrease in white matter affecting connection between frontal lobe and amygdala (except for medial-prefrontal connection, which is linked to empathy and the only structure still well connected to the amygdala) Link to Chromosome 7 (next slide) suggests involvement in parietal, occipital, and/or white matter in CNS

Elastin protein, made only during the prenatal period, is absent and causes vascular problems during life; the missing elastin gene is use to identify the 21 missing genes in Williams Syndrome.

Genetic Abnormality of Chromosome 7: 21 genes missing

Autism
A neurodegenerative disorder characterized by impairment in social interaction and communication.
Age of onset: typically between ages 2 and 4 (sometimes earlier)

Symptoms

Theories for Etiology and CNS Problems

Genetic alterations Prenatal exposure to toxins and/or viruses Maternal and fetal immune interactions Vaccination with mercury base
Amygdala less active and area is smaller Hippocampus is smaller Frontal areas (medial prefrontal region) less active Less activity in the superior temporal sulcus (involved in understanding others) Larger & heavier brain suggests apoptosis failure

Microglia Activation in Autism (white matter of the cerebellum)

Microglial cells

Brain Areas Affected in Autism: Fusiform Face Area (FFA), Amygdala, Left Frontal Lobe, Left Temporal Lobe, and Cerebellum

References for Photos

http://images.google.com/imgres?imgurl=http://www.hallym.or.kr/~kdcp/cytogenetics/cytogends.files/c6_cleft_lip.jpg&imgrefurl=http://www.hallym.or.kr/~kdcp/cytogenetics/cytogends.htm&h=483&w=316&sz=61&tbnid=9z1GFXy5kykJ:&tbnh=126&tbnw=82&hl=en&start=61&prev=/images%3Fq%3DWilliams%2BSyndrome%26start%3D60%26svnu m%3D10%26hl%3Den%26lr%3D%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official_s%26sa%3DN http://images.google.com/imgres?imgurl=http://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%2520Images/gen12.gif&imgrefurl=http://cas.bellarmine.edu/tietjen/Hu manBioogy/bills_developmental_abnormalities.htm&h=383&w=400&sz=117&tbnid=KbFuC4QsI4sJ:&tbnh=114&tbnw=120&hl=en&start=3&prev=/images%3Fq%3DEdw ard%2527s%2BSyndrome%26svnum%3D10%26hl%3Den%26lr%3D%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official_s%26sa%3DG http://images.google.com/imgres?imgurl=http://www.cmu.edu/cmnews/extra/extra_art/Just_Fig1.jpg&imgrefurl=http://www.cmu.edu/cmnews/extra/extra_art/&h=421&w= 150&sz=25&tbnid=0aXX65rnVysJ:&tbnh=122&tbnw=43&hl=en&start=189&prev=/images%3Fq%3Dautism%2Bbrain%26start%3D180%26svnum%3D10%26hl%3Den %26lr%3D%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official%26sa%3DN http://www.altcorp.com/DentalInformation/autismcytokines.htm http://www.neuro.jhmi.edu/neuroimmunopath/Microglia%20pictures/5_lg.jpg

http://images.google.com/imgres?imgurl=http://www.fetalalcohol.com/images/face-thm.gif&imgrefurl=http://www.fetalalcohol.com/what-isfase.htm&h=260&w=304&sz=16&tbnid=RpmOv4g5G04J:&tbnh=95&tbnw=112&hl=en&start=6&prev=/images%3Fq%3DFetal%2BAlcohol%2BSy ndrome%26svnum%3D10%26hl%3Den%26lr%3D%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official_s%26sa%3DG http://images.google.com/imgres?imgurl=http://www.infobiogen.fr/services/chromcancer/IntroItems/Images/tri21FaceEng.gif&imgrefurl=http://www .infobiogen.fr/services/chromcancer/IntroItems/PolyTri21Eng.html&h=429&w=463&sz=50&tbnid=XGXbYU9uVcYJ:&tbnh=115&tbnw=125&hl=en& start=1&prev=/images%3Fq%3DTrisomy%2B21%2Bface%26svnum%3D10%26hl%3Den%26lr%3D%26client%3Dfirefoxa%26rls%3Dorg.mozilla:en-US:official_s%26sa%3DG