Development of the NS

1. Development of the NS • start with a single cell that begins to divide!

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

3. 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

4. How do neurons get to where they need to be? • cortex has multiple layers with different size/shape neurons - • radial glia in cortex

5. Other regions - • growth cones and “lamellipodia” • cell attractants and repellants

6. 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!!!

7. Some things that happen during CNS development • apoptosis – “programmed cell death” • what controls apoptosis • many things! • activity • drugs? • environment?

8. 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!

9. 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

10. 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.

11. 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

13. Developmental Issues Following Fetal Alcohol Exposure

14. 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)

15. 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 13:7

16. 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, 132:419, 1946 • Ethanol drip was used to treat premature labor. • 1973: First scientific paper naming Fetal Alcohol Syndrome

17. 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?

18. Fetal Alcohol Syndrome: Diagnostic Criteria • Pre- and/or postnatal growth deficiency • Evidence of central nervous system dysfunction • Specific pattern of facial features

19. FAS: Characteristic Facial Features Streissguth, 1994

20. 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

21. Fetal Alcohol Spectrum Disorders (FASD) ARND: Alcohol-Related Neurodevelopmental Disorder ARBD: Alcohol-Related Birth Defects

22. 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

23. 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 .

24. 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

26. 115 100 85 70 55 40 General Intellectual Performance NC PEA * * * * FAS * ** Standard score FSIQ VIQ PIQ IQ scale

27. Executive functioning deficits 6 NC PEA 4 FAS Rule Violations P<0.001 2 1 2 0 Group 3 Move only one piece at a time using one hand and never place a big piece on top of a little piece 1 3 2 Starting position Ending position Mattson, et al., 1999

28. Behavioral characteristics associated with Fetal Alcohol Spectrum Disorder • hyperactivity, response inhibition deficits, attentional problems, motor coordination deficits, executive function (planning) problems,

29. Clinical Implications….. • Easily victimized • unfocused or distractible • difficulty handling $$ • difficulty learning from experience • difficulty under-standing consequences • poor frustration tolerance • Poor judgement • Attention deficits • Arithmetic disabilities • Memory deficits • Problems with abstract thought • Impulsivity

30. Secondary Disabilities of Persons With an FASD Percent of Persons With FAS or FAE Who Had Secondary Disabilities  = Age 6+ = Age 12+ = Age 21+

31. Evidence for CNS damage • plenty of data • cerebellum • cerebral cortex • corpus callosum • basal ganglia

32. Brain damage resulting from prenatal alcohol photo: Clarren, 1986

34. Cerebrum Cerebellum 100 PEA 95 FAS 90 *** p < 0.001 ** p < 0.010 85 80 75 Change in brain size Cerebrum Cerebellum Corpus Callosum Mattson et al., 1994

35. Corpus callosum abnormalities Mattson, et al., 1994; Mattson & Riley, 1995; Riley et al., 1995

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

37. Body and Brain Develop inDifferent Stages in Pregnancy

38. 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;

39. Alcohol-Exposed Rodent Models Show Same Behavioral Deficits Hyperactivity Motor Deficits

40. 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

41. Pharmacotherapy and/or environmental manipulations • environmental enrichment

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

43. 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