Development of the NS

start with a single cell that begins to divide!

Neurulation

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

Neurulation

http://worms.zoology.wisc.edu/frogs/neuru/keller_neur.html

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

How do neurons get to where they need to be?

cortex has multiple layers with different size/shape neurons -

radial glia in cortex

Neuronal migration in cortex

http://rakiclab.med.yale.edu/pages/corticalNeuronMigration.php

http://www.youtube.com/watch?v=ZRF-gKZHINk&feature=PlayList&p=B3AD14F3484810FE&playnext=1&playnext_from=PL&index=24

Other regions -

growth cones and “lamellipodia”cell attractants and repellants

http://www.youtube.com/watch?v=Fgmt2RBow0I&feature=related

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!!!

Some things that happen during CNS development

apoptosis – “programmed cell death” what controls apoptosis

many things! activity drugs? environment?

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!

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?v=FuWWie1DlJY

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.

Incidence of autism

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

Developmental Issues Following Fetal Alcohol Exposure

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)

Historical View of Alcohol as a Historical View of Alcohol as a TeratogenTeratogen

““Foolish, drunken, or Foolish, drunken, or harebrain women most harebrain women most often bring forth children often bring forth children like unto themselves” like unto themselves”

Aristotle in Aristotle in ProblemataProblemata

““Behold, thou shalt conceive Behold, thou shalt conceive and bear a son: And now, and bear a son: And now, drink no wine or strong drink no wine or strong drink.”drink.”

Judges 13:7Judges 13:7

• “… “… the idea of germ poisoning by alcohol in the idea of germ poisoning by alcohol in humans may be safely dismissed…” humans may be safely dismissed…”

Journal of Studies on Alcohol, 1, 1940 Journal of Studies on Alcohol, 1, 1940

• ““The offspring of alcoholics have been found The offspring of alcoholics have been found defective not because of alcoholism of the parents defective not because of alcoholism of the parents but because the parents themselves came from a but because the parents themselves came from a defective stock.”defective stock.” Journal American Medical Association, 132:419, Journal American Medical Association, 132:419, 1946 1946

• Ethanol drip was used to treat premature labor. Ethanol drip was used to treat premature labor.

• 1973: First scientific paper naming Fetal Alcohol 1973: First scientific paper naming Fetal Alcohol SyndromeSyndrome

Alcohol as a Teratogen: 20th Century

Fetal Alcohol SyndromeFetal Alcohol Syndrome

Fetal alcohol syndrome is Fetal alcohol syndrome is the leading preventable the leading preventable cause of mental retardation.cause of mental retardation.

What is it, how does it affect What is it, how does it affect people, what can we do people, what can we do about it? about it?

Fetal Alcohol Syndrome: Diagnostic Criteria

Pre- and/or postnatal Pre- and/or postnatal growth deficiencygrowth deficiency

Evidence of central Evidence of central nervous system nervous system dysfunctiondysfunction

Specific pattern of Specific pattern of facial featuresfacial features

Streissguth, 1994

FAS: Characteristic Facial FAS: Characteristic Facial FeaturesFeatures

FAS – Only the tip of the icebergFAS – Only the tip of the iceberg

Fetal alcohol Fetal alcohol syndromesyndrome

Fetal alcohol effectsFetal alcohol effects

Clinical suspect but Clinical suspect but appear normalappear normal

Normal, but never Normal, but never reach their potentialreach their potential

Adapted from Streissguth

Fetal Alcohol Spectrum Disorders (FASD)

ARND: Alcohol-Related Neurodevelopmental Disorder

ARBD: Alcohol-Related Birth Defects

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

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

.

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

Data from recent CDC report

FSIQ VIQ PIQ40

55

70

85

100

115

Sta

nd

ard

score

IQ scale

NC

PEA

FAS*

**

**

**

General Intellectual Performance

2

1

3

1

2

3

Group0

2

4

6

Ru

le V

iola

tion

s NC

PEA

FAS

P<0.001

Move only one piece at a time using one hand and never place a big piece on top of a little piece

Starting position

Ending positionMattson, et al., 1999

Executive functioning deficits

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

Behavioral characteristics associated with Fetal Alcohol Spectrum Disorder

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

Clinical Implications…..

Secondary Disabilities of Persons With an FASD

= Age 6+ = Age 12+ = Age 21+

Percent of Persons With FAS or FAE Who Had Secondary Disabilities

Evidence for CNS damage

plenty of data

cerebellum cerebral cortex corpus callosum basal ganglia

Brain damage resulting from prenatal alcohol

photo: Clarren, 1986

*** **

Cerebrum Cerebellum

75

80

85

90

95

100

PEA

FAS <p 0.001

p < 0.010

Cerebrum

CerebellumCorpus Callosum

Mattson et al., 1994

Change in brain size

Corpus callosum abnormalities

Mattson, et al., 1994; Mattson & Riley, 1995; Riley et al., 1995

Risk FactorsRisk Factors

Dose of alcoholDose of alcohol Pattern of exposure - binge vs chronicPattern of exposure - binge vs chronic GeneticsGenetics Maternal characteristicsMaternal characteristics Reactions with other drugsReactions with other drugs NutritionNutrition Developmental timing of exposureDevelopmental timing of exposure

Body and Brain Develop inDifferent Stages in Pregnancy

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

Animal models – Example of the comparability of effects

Driscoll, et al., 1990; Samson, 1986;

Alcohol-Exposed Rodent Models Show Same Behavioral Deficits

Hyperactivity Motor Deficits

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

Pharmacotherapy and/or environmental manipulations

environmental enrichment

EE

Reduces many of the behavioral deficits reported

increases dendritic spines (in controls and drug treated)

Pharmacological manipulations

drugs that increase cholinergic activity reduce glutamate activity

just naming a few – seem to reduce some of alcohol’s effects on the developing brain