Development of the NS

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Development of the NS

• start with a single cell that begins to divide!

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Neurulation

• Gives rise to neural tube (which gives rise to
  the CNS)

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Neurulation

• http//worms.zoology.wisc.edu/frogs/neuru/keller_n
  eur.html

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CNS development

• What determines what and where a neuron should
  be?
• very complicated numerous models pluripotent
  (versatile) to begin with
• role of nearby chemical factors that can
  influence things

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How do neurons get to where they need to be?

• cortex has multiple layers with different
  size/shape neurons -
• radial glia in cortex

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Neuronal migration in cortex

• http//rakiclab.med.yale.edu/pages/corticalNeuronM
  igration.php
• http//www.youtube.com/watch?vZRF-gKZHINkfeature
  PlayListpB3AD14F3484810FEplaynext1playnext_f
  romPLindex24

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Other regions -

• growth cones and lamellipodia
• cell attractants and repellants

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• http//www.youtube.com/watch?vFgmt2RBow0Ifeature
  related

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• Once neuron reaches destination it needs to
• form synaptic connections
• make neurotransmitter
• elongate its axon
• make postsynaptic and presynaptic receptors
• JUST TO NAME A FEW THINGS!!!

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Some things that happen during CNS development

• apoptosis programmed cell death
• what controls apoptosis
• many things!
• activity
• drugs?
• environment?

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Amazing it all works!!!!

• two disorders where brain development does not go
  quite as planned
• autism and Fetal Alcohol Syndrome
• similar in that these both involve changes in
  brain during developmental
• developmental disorders
• differences
• one is preventable!

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Autism

• characteristics
• Delayed or unusual speech patterns
• High pitched or flat intonation
• Lack of slang or "kidspeak"
• Difficulty understanding tone of voice and body
  language as a way of expressing sarcasm, humor,
  irony, etc.
• Lack of eye contact
• Inability to take another's perspective (to
  imagine oneself in someone else's shoes)
• hypo or hypersensitive to environmental stimuli
• http//www.youtube.com/watch?vFuWWie1DlJY

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Additional personality characteristics

• Engage in repetitive behaviors and ritualized
  activities, ranging from lining up items to
  following a rigid routine OCD symptoms
• Have one or a few passionate interests,
• Have difficulty in making and keeping multiple
  friends,
• Prefer activities that require relatively little
  verbal interaction.

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Incidence of autism
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Evidence for CNS?

• possible deficits in complex or higher order
  cognitive abilities
• evoked potentials
• auditory and visual ERPs altered
• processing of emotional facial expressions
• - ERPs

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Developmental Issues Following Fetal Alcohol
Exposure
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Definitions

• Teratogen a substance capable of interfering
  with fetal development
• Teratology the biological study of birth defects
• Behavioral Teratology the study of how agents
  can affect behavior (so affects brain)

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Historical View of Alcohol as a Teratogen

• Foolish, drunken, or harebrain women most often
  bring forth children like unto themselves
  Aristotle in Problemata
• Behold, thou shalt conceive and bear a son And
  now, drink no wine or strong drink.
• Judges 137

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Alcohol as a Teratogen 20th Century

• the idea of germ poisoning by alcohol in
  humans may be safely dismissed
• Journal of Studies on Alcohol, 1, 1940
• The offspring of alcoholics have been found
  defective not because of alcoholism of the
  parents but because the parents themselves came
  from a defective stock.
• Journal American Medical Association,
  132419, 1946
• Ethanol drip was used to treat premature labor.
• 1973 First scientific paper naming Fetal Alcohol
  Syndrome

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Fetal Alcohol Syndrome
Fetal alcohol syndrome is the leading preventable
cause of mental retardation. What is it, how
does it affect people, what can we do about it?
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Fetal Alcohol Syndrome Diagnostic Criteria

• Pre- and/or postnatal growth deficiency
• Evidence of central nervous system dysfunction
• Specific pattern of facial features

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FAS Characteristic Facial Features
Streissguth, 1994
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FAS Only the tip of the iceberg

• Fetal alcohol syndrome
• Fetal alcohol effects
• Clinical suspect but appear normal
• Normal, but never reach their potential

Adapted from Streissguth
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Fetal Alcohol Spectrum Disorders (FASD)
ARND Alcohol-Related Neurodevelopmental
Disorder ARBD Alcohol-Related Birth Defects
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Statistics

• Approximately 1 FAS birth out of 1000 live births
  in the US
• Approximately 3-6 FASD births out of 1000 live
  births in the US
• Estimated costs 2.8 billion/year

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Cause of FASD

• The sole cause of FASD is women drinking
  alcoholic beverages during pregnancy.
• Alcohol is a teratogen.

Of all the substances of abuse (including
cocaine, heroin, and marijuana), alcohol produces
by far the most serious neurobehavioral effects
in the fetus. IOM Report to Congress,
1996 .
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Data from recent CDC report

• more than 130,000 pregnant women/yr in US drink
  at levels that may increase risk of FAS
• rates of frequent and binge drinking in pregnant
  women have NOT declined in the last 8 years

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General Intellectual Performance

NC
PEA




FAS


Standard score
FSIQ
VIQ
PIQ
IQ scale
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Executive functioning deficits
Move only one piece at a time using one hand and
never place a big piece on top of a little piece
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3
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Starting position
Ending position
Mattson, et al., 1999
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Behavioral characteristics associated with Fetal
Alcohol Spectrum Disorder

• hyperactivity, response inhibition deficits,
  attentional problems, motor coordination
  deficits, executive function (planning) problems,

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Clinical Implications..

• Poor judgement
• Attention deficits
• Arithmetic disabilities
• Memory deficits
• Problems with abstract thought
• Impulsivity

• Easily victimized
• unfocused or distractible
• difficulty handling
• difficulty learning from experience
• difficulty under-standing consequences
• poor frustration tolerance

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Secondary Disabilities of Persons With an FASD
Percent of Persons With FAS or FAE Who Had
Secondary Disabilities
? Age 6 ? Age 12 ? Age 21
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Evidence for CNS damage

• plenty of data
• cerebellum
• cerebral cortex
• corpus callosum
• basal ganglia

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Brain damage resulting from prenatal alcohol
photo Clarren, 1986
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Change in brain size
Cerebrum
Cerebellum
Corpus Callosum
Mattson et al., 1994
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Corpus callosum abnormalities
Mattson, et al., 1994 Mattson Riley, 1995
Riley et al., 1995
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Risk Factors

• Dose of alcohol
• Pattern of exposure - binge vs chronic
• Genetics
• Maternal characteristics
• Reactions with other drugs
• Nutrition
• Developmental timing of exposure

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Body and Brain Develop inDifferent Stages in
Pregnancy
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Animal models Example of the comparability of
effects

• Growth retardation
• Facial characteristics
• Heart, skeletal defects
• Microcephaly
• Reductions in basal ganglia and cerebellar
  volumes
• Callosal anomalies

• Hyperactivity, attentional problems
• Inhibitory deficits
• Impaired learning
• Perseveration errors
• Feeding difficulties
• Gait anomalies
• Hearing anomalies

Driscoll, et al., 1990 Samson, 1986
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Alcohol-Exposed Rodent Models Show Same
Behavioral Deficits
Hyperactivity Motor Deficits
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Interventions

• protective factors
• interventions and stable environment and
  guardianship (for kids as they grow up)
• numerous programs exist maybe not enough but
  progress is being made

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Pharmacotherapy and/or environmental manipulations

• environmental enrichment

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EE

• Reduces many of the behavioral deficits reported
• increases dendritic spines (in controls and drug
  treated)

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Pharmacological manipulations

• drugs that
• increase cholinergic activity
• reduce glutamate activity
• just naming a few seem to reduce some of
  alcohols effects on the developing brain