Development of the NS

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

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

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

7. 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

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

9. 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

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

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

12. 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!!!

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

14. 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!

15. 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

16. 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.

17. Incidence of autism

18. 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

22. Developmental Issues Following Fetal Alcohol Exposure

23. 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)

24. 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

25. 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

26. 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?

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

28. FAS: Characteristic Facial Features Streissguth, 1994

29. 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

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

31. 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

32. 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 .

33. 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

35. 115 100 85 70 55 40 General Intellectual Performance NC PEA * * * * FAS * ** Standard score FSIQ VIQ PIQ IQ scale

36. 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

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

38. 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

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

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

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

43. 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

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

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

46. Body and Brain Develop inDifferent Stages in Pregnancy

47. 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;

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

49. 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

50. Pharmacotherapy and/or environmental manipulations • environmental enrichment