The Effects of Prenatal Alcohol Exposure on Brain and Behavior

1. The Effects of Prenatal Alcohol Exposure on Brain and Behavior Edward Riley Center for Behavioral Teratology and Department of Psychology San Diego State University San Diego, CA Alcohol and Pregnancy: An Overview of Fetal Alcohol Spectrum Disorders A Congressional Briefing Sponsored by The FRIENDS OF NIAAA Wednesday, May 20, 2009

2. Fetal Alcohol Syndrome In the early 1970’s case reports began appearing describing the consequences of heavy maternal alcohol use during pregnancy. The offspring were noted to have distinctive facial characteristics. They were also small for gestation age and had poor postnatal growth. Also evidenced disorders of the central nervous system. Photo courtesy of T. Kellerman

3. Associated Features Epicanthal folds Short palpebral fissure Low nasal bridge Minor ear anomalies Indistinct philtrum Thin upper lip Micrognathia Facies in Fetal Alcohol Syndrome Discriminating Features In the young child Streissguth, 1994

4. Examples of Children with FAS Short palpebral fissure Indistinct philtrum Thin upper lip *

5. Example of extreme brain damage resulting from prenatal alcohol exposure CNS anomalies 

6. Soon after the identification of FAS researchers confirmed that alcohol was a teratogen in animal models ranging from mice and rats to dogs, miniature swine, and primates. • These models were important because case reports were confounded by numerous variables that could not be well controlled. • smoking, SES, poor prenatal care

7. Child with FAS Comparison: Child with FAS and mouse fetus with fetal alcohol exposure Mouse fetuses Small head Short palpebral fissures Small nose Small midface Long philtrum; Thin upper lip * alcohol-exposed normal Photos courtesy of K. Sulik

8. Critical Periods of Development

9. FAS – Only the tip of the iceberg • Fetal alcohol effects ARND/ARBD • Appear normal but clinical suspect • Fetal alcohol syndrome Fetal alcohol spectrum disorder(s)

10. 60 50 40 Binge 30 Any Use 20 10 0 2001 2002 2003 2004 2005 Alcohol Consumption Prevalence Among Non-Pregnant Women 18-44 years Binge: ≥ 5 drinks on one occasion in past month Any Use: 1 or more drinks in past month Source: Behavioral Risk Factor Surveillance System 2001-2005, CDC.

11. 14 12 10 8 Binge 6 Any use 4 2 0 2001 2002 2003 2004 2005 Alcohol Consumption Prevalence Among Pregnant Women 18-44 years Binge: ≥ 5 drinks on one occasion in past month Any Use: 1 or more drinks in past month Source: Behavioral Risk Factor Surveillance System 2001-2005, CDC.

12. Estimates about costs • FAS costs US $5.4 billion in direct and indirect costs in 2003 • $3.9 billion in direct costs (Actual use of goods and services) • $1.5 billion in indirect costs (Lost potential productivity) • An FAS birth carries lifetime health costs of just under a million dollars, although it can be as high as 4.2 million. • Even “expensive” FAS prevention may have a large cost/benefit ratio.

13. Take Home Message 1 Prenatal exposure to alcohol, at least high doses of alcohol, can cause permanent changes in the brain 

14. Alcohol can act as a behavioral teratogen Prenatal exposure to alcohol can result in a variety of behavioral dysfunctions, even in the absence of obvious physical effects. Take Home Message 2 

15. MRI Investigation of Children with FASD

16. Surface rendering T1-Weighted Skull stripped tissue segmented Image Analysis *

17. Fetal Alcohol Syndrome (FAS) - Dysmorphic FASD Children with all of the required diagnostic criteria and a confirmed history of heavy prenatal alcohol exposure Prenatal Exposure to Alcohol (PEA) - Non Dysmorphic FASD Children with a known history of significant alcohol exposure, but without the physical features necessary for a diagnosis of FAS Non-exposed Control (CON) Children who have no history of exposure to alcohol or other known teratogens Diagnostic Groups

18. Given overall changes in brain size, we would expect to see global deficits Given changes in cerebellum, we would expect to see changes in balance, motor skills, timing, attention, and classical conditioning

19. 115 NC FAS * 100 * * * * ** 85 Standard score 70 55 NDFASD 40 FSIQ VIQ PIQ IQ scale Mattson, S.N., 1997. General Intellectual Performance FAS is the leading known cause of mental retardation in the western world, but the majority are not retarded *

20. NC NDFASD FAS * * * Language Test Performance 130 60 115 50 100 40 Standard score * Raw score 85 30 * 70 20 55 10 40 0 PPVT-R BNT Language Measure *

21. * 135 * NDFASD FAS 120 * * Time (sec.) 105 90 75 60 Fine-Motor Skill:Grooved Pegboard Test 150 NC Dominant Nondominant Hand 

22. Neuropsychological Performance *

23. Controls 150000 p = .0003* FAS 120000 90000 p = .0002* Volume p = .018 60000 p = .030 30000 0 Frontal Temporal Parietal Occipital Lobe Lobe Analysis * * Significant after controlling for overall brain size

24. The parietal lobe is involved in math and visual spatial domains therefore we would expect to see deficits in these domains

25. Math Disabilities • Math skills more impaired than language • Can be observed in preschool period and persists through adulthood • Probably related to visual/spatial deficits • Also related to executive functioning problems Howell, et al (2006) J Ped Psych Kable and Coles-Fudge, MILE Streissguth’s cohort Jacobson and Jacobson

26. Controls PEA FAS Virtual Water Maze - Probe Trial Paths *

27. The frontal lobes, making logical decisions 

28. Executive function Judgment Difficulty in interpreting feedback from the environment Risk taking Non-compliance with rules Impaired associated learning Spontaneity Memory Social and sexual behavior Some aspects of language Role of frontal lobes

29. Caudate* Accumbens* Thalamus Frontal Cortex 100 95 90 85 * 80 NDFASD 75 Striatum (caudate & putamen) FAS Globus Pallidus (part of lenticular nucleus) *** 70 Frontal Subcortical Circuits

30. The Basal Ganglia (Caudate) and other Subcortical Structures • Relays information to frontal lobes • Organize and prioritize information • Filters information • Category learning • Emotional gating • Working memory

31. “We wondered how a child could get A’s in school and not have the sense to understand that when she is rude to friends they might get mad at her.” -Hilary O’Loughlin (Iceberg, 1995) * 

32. Executive Functioning Cognitive functions involved in planning and guiding behavior in order to achieve a goal in an efficient manner. • The ability to organize and plan • Focus and maintain attention • Be able to store memories and retrieve them • Issues related to affect and inhibition, e.g. preventing anger from getting out of control • Self-awareness • Initiating and ending activities *

33. 10 NC 8 PEA 1 3 FAS 2 6 Items passed 4 Starting position 2 0 Group 1 2 6 NC 3 5 PEA 4 FAS Ending position Rule Violations 3 Move only one piece at a time using one hand and never place a big piece on top of a little piece 2 1 0 Group Executive FunctioningTower of California Test *

34. Twenty Questions (Concept Formation) • Normal responses • Is it alive? • Is it on the left of the page? • Can you eat it? • Is it the banana?

35. Cerebrum Cerebellum Corpus Callosum The Corpus Callosum • Connects the left and right halves of the brain • Allows them to work together and put information together 

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

37. NDFASD CON FAS Reductions in Corpus Callosum Area *

38. White versus gray matter • The white matter coating our nerves. Composed of a layer of proteins packed between two layers of lipids. • Produced by specialized cells: oligodendrocytes in the CNS. Myelin sheaths wrap themselves around axons, the threadlike extensions of neurons that make up nerve fibers. • Make nerve conduction faster.

39. 13 yr old male with FAS DT TRACTOGRAPHY Combining DTI data with computational methods of tractography, the locations and sizes of white matter pathways can be estimated 13 yr old male control seed volume placed in the splenium of the CC

40. Right Brain Left Brain • Spatial abilities • Face recognition • Visual imagery • Music • Language • Math • Logic Left brain/Right brain The Corpus Callosum

41. Stimuli Y Y Y Y Y Y Y Y Y D Y Y Y Controls Alcohol-exposed Alcohol-exposed What each half of the brain sees What each half of the brain sees *

42. Given changes in numerous brain areas we would expect significant differences in complex behaviors For example, social behavior is contingent on numerous brain areas • Orbitofrontal cortex, amygdala, insula, medial prefrontal cortex and temporoparietal junction

43. Social Functioning in FASD Deficits in social functioning above and beyond IQ or other behavioral problems Difficulty meeting age-related expectations Quality of social interactions is often poor or inappropriate

44. Reductions in overall brain size and in certain brain structures or areas, e.g. the cerebellum (anterior vermis), basal ganglia (caudate), corpus callosum, parietal-temporal region To much gray matter and lesser amounts of white matter in some areas (i.e. DTI). Decrease in white matter integrity. Distortions in shape of brain (front too blunt, sides too narrow) Cortex too thick in places Changes in energy metabolism (MRS), changes in function noted in fMRI, changes in functional connectivity Brain imaging data correlate with both physical an behavioral outcomes Summary of MRI Findings

45. These changes in brain may cause or contribute to many of the behavioral problems seen in individuals exposed to alcohol. These changes in brain appear to be the result of prenatal alcohol exposure, although some areas may also be affected by postnatal experiences Knowing what brain areas are involved might enable us to develop better treatment strategies. Prenatal exposure to alcohol, at least in high doses, can cause permanent changes in the brain

46. Heavy prenatal alcohol exposure is associated with a wide range of neurobehavioral deficits Children with and without physical features of the fetal alcohol syndrome display qualitatively similar deficits A specific pattern of relative strengths and weaknesses may exist or there may be several patterns Identification of children with heavy prenatal alcohol exposure is critical. Research has shown that early identification leads to interventions, services and improved outcomes. Summary of Neuropsychological Findings

48. Thank You Edward Riley 6363 Alvarado Ct. #209 San Diego, CA 92120 eriley@mail.sdsu.edu