Ethanol and the Developing Brain: Molecular, Neurochemical & Cellular Impacts

1. Ethanol and the Developing Brain: Molecular, Neurochemical & Cellular Impacts Josephine F. Wilson, D.D.S., Ph.D. Professor of Community Health Director, Substance Abuse Resources and Disability Issues (SARDI) Program Boonshoft School of Medicine

2. The Vulnerable Brain ETHANOL GLUCOSE

3. Metabolites of Ethanol FORMALDEHYDE ACETALDEHYDE Reactive Oxygen Species Oxidative Stress Free Radical-Mediated Damage

4. Alcohol Consumption During Pregnancy • The leading preventable cause of birth defects and neurodevelopmental disorders • Most severe: fetal alcohol syndrome (FAS) • A continuum of physical anomalies and behavioral and cognitive deficits: fetal alcohol spectrum disorders (FASD) • Some brain areas or cell populations more vulnerable than others

5. FASD: Behavioral and Cognitive Deficits • General intelligence • Memory • Language • Attention • Learning • Visuospatial abilities • Executive functioning • Fine and gross motor skills • Hyperactive, disruptive, impulsive, delinquent • Depression, anxiety disorders, suicidal ideation, suicide attempts • Social and adaptive functioning • Academic achievement

6. Biological and Environmental Factors • Dose of alcohol exposure • Exposure pattern (binge vs. chronic) • Developmental timing of exposure • Genetic background of mother/fetus • Maternal nutrition • Ingestion of other drugs BAL > 200 mg/dL versus BAL < 150 mg/dL alcohol dehydrogenase (ADH) allelle

7. Brain Development • Gastrulation • Proliferation • Migration • Cell differentiation • Dendritic and axonal growth • Programmed cell death

9. Craniofacial Defects of FAS

10. Effects of Damage to the Developing Brain

11. Cerebrum

12. Cerebellum • Develops rapidly in 3rd trimester • Tremors, weak grasp, poor eye/hand coordination, gait and balance difficulties, poor motor response programming, reaction time

13. White Matter Defects Gray Matter = Neurons White Matter = Glial cells

14. Corpus Callosum Normal Brain Complete Agenesis Partial Agenesis

15. Developing Brain Systems Affected by Alcohol • Serotonin system • Dopamine system • GABA system • Glutamate system • Adrenergic system

16. Alterations Produced by Ethanol • Gene alterations Epigenetic modification • Alterations in mitogenic and growth factors Neurotrophins • Alterations in molecules Cell-adhesion molecules • Oxidative stress Reduced antioxidant levels • Alterations in molecular signaling Cell survival • Alterations in glial proliferation, differentiation, and functioning

17. The Developing Brain • By the age of 5 or 6, the brain usually has reached about 95 percent of the average adult volume, having increased fourfold in size since birth. • From ages 3 to 6, the most rapid growth takes place in frontal-lobe areas involved in planning and organizing new actions, and in maintaining attention to tasks. • From 6 to puberty, the gray-matter spike shifts to the temporal and parietal lobes that play a major role in language skills and spatial relations. • Increase in gray matter in the frontal lobes at the onset of adolescence, followed by a substantial loss in the frontal lobes from the mid-teens through the mid-twenties. • Gray matter is replaced by white matter.

18. The Adolescent Brain • 30 – 56% of 16-year-olds binge drink • more vulnerable to disruption from binge drinking • “blackouts” • neural plasticity in prefrontal cortex and hippocampus • rapid maturation of brain reward systems • changes in secretion of stress hormones

19. Positron Emission Tomography PET Wallace Kettering Neuroscience Institute 3533 Southern Boulevard Kettering, OH

20. Literature Review PET studies have revealed that glucose metabolism is reduced in the brains of chronic alcoholics • Goldstein, Leskovjan, Hoff, Hitzemann, Bashan, Khalsa, Wang, Fowler, & Volkow (2004) • Dao-Castelanna, Samson, Legault, Martinot, Aubin, Crouzel, Feldman, Barrucand, Rancurrel, Feline, & Syrota (1998) • Johnson-Greene, Adams, Gilman, Koeppe, Junck, Kluin, Martello, & Heumann (1997) • Volkow, Wang, Overall, Hitzemann, Fowker, Pappas, Frecska, & Piscani (1997) • Adams, Gilman, Koeppe, Kluin, Brunberg, Dede, Berent, & Kroll (1993)

22. Design Two groups of subjects • 10 men, 21-25 years old, who drink at least 25 drinks per week • 10 men, 21-25 years old, who abstain from drinking alcohol

23. Experimental Participants Selected on the Basis of Four Criteria • They drink the equivalent of twenty-five drinks per week and are binge drinkers, as opposed to daily drinkers. • They have been drinking heavily for more than two years. • They do not use other drugs (e.g., marijuana). • They do not have significant psychiatric histories that require the use of medications with potential to affect cognitive function.

24. Procedure • PARTICIPANT SCREENING Day 1: • URINE and BLOOD TESTS • PHYSICAL EXAMINATION • NEUROPSYCHOLOGICAL EXAM • PET SCAN Day 2: • URINE and BLOOD TESTS • PET SCAN • MRI SCAN

25. Screening Criteria • Age: • Do you drink?_________ if yes: how much?______ everyday?_______ over weekend?_______ how long have you been drinking?_________ can you go 48 hours without drinking?__________ do you experience tolerance? (drink more for same effect)______ have you ever tried to quit/cut down?_______ do you spend a great deal of time getting, using, and/or recovering?________ have you given up/reduced activities for drinking?________ do you continue to drink despite health problems?_____ • Are you taking and medications for psychological/brain disorders? (anti-depressants, anti-epileptic, ADD medication). ____________ • Have you ever had a head injury or been knocked unconscious in an accident or sporting event? _______ • Do you take any non-prescription drugs?__ Marijuana?__ Cocaine?__

26. PET Imaging with FDG 18F-Fluorodeoxyglucose – fluoride isotope • Quantitative measurement of the regional rate of glucose metabolism (rCMRGIc) • Approximately 8 mCi of 18F-FDG is injected in each subject for each scan. • Emission data is acquired over a 15 minute interval approximately 45 minutes post-injection of 18F-FDG

27. MRI provides anatomical information

28. Co-Registration Process PET MR

30. Co-Registered

31. PET scans

32. PET scans

33. PET scans

34. Summary Deficits associated with FASD: • General intelligence – frontal lobes • Memory, language, attention, learning – frontal lobes • Visuospatial abilities – parietal lobes • Fine and gross motor skills - cerebellum • Hyperactive, disruptive, impulsive, delinquent - frontal • Depression, anxiety disorders, suicidal ideation, suicide attempts – frontal lobes, limbic system, basal ganglia • Social and adaptive functioning – frontal lobes • Academic achievement – frontal lobes, hippocampus

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36. References Alfonso-Loeches S, Guerri C. Molecular and behavioral aspects of the actions of alcohol on the adult and developing brain. Critical Reviews in Clinical Laboratory Sciences 2011 Jan-Feb;48(1):19-47. Paton, S. J., & Croom, C. S. An Overview of Fetal Alcohol Spectrum Disorders for Physicians.(Disease/Disorder overview). Primary Care Reports, January 1, 2010. Manning MA, Eugene Hoyme H. Fetal alcohol spectrum disorders: a practical clinical approach to diagnosis. NeurosciBiobehav Rev. 2007;31(2):230-8. Epub 2006 Sep 7. Jones KL. The effects of alcohol on fetal development. Birth Defects Res C Embryo Today. 2011 Mar;93(1):3-11. Riley EP, Infante MA, Warren KR. Fetal alcohol spectrum disorders: an overview. Neuropsychol Rev. 2011 Jun;21(2):73-80. Epub 2011 Apr 16.