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

The Vulnerable Brain

GLUCOSE ETHANOL

Metabolites of Ethanol

FORMALDEHYDE ACETALDEHYDE

Reactive Oxygen Species Oxidative StressFree Radical-Mediated Damage

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

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

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/dLalcohol dehydrogenase (ADH) allelle

Brain Development

• Gastrulation• Proliferation • Migration• Cell differentiation • Dendritic and axonal growth• Programmed cell death

Craniofacial Defects of FAS

Effects of Damage to the Developing Brain

Cerebrum

Cerebellum

• Develops rapidly in 3rd trimester• Tremors, weak grasp, poor eye/hand

coordination, gait and balance difficulties, poor motor response programming, reaction time

White Matter Defects

Gray Matter = NeuronsWhite Matter = Glial cells

Corpus Callosum

Normal Brain Complete AgenesisPartial Agenesis

Developing Brain Systems Affected by Alcohol

• Serotonin system• Dopamine system• GABA system• Glutamate system• Adrenergic system

Alterations Produced by Ethanol

• Gene alterationsEpigenetic modification

• Alterations in mitogenic and growth factorsNeurotrophins

• Alterations in moleculesCell-adhesion molecules

• Oxidative stressReduced antioxidant levels

• Alterations in molecular signalingCell survival

• Alterations in glial proliferation, differentiation, and functioning

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.

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

Positron Emission Tomography

PET

Wallace Kettering Neuroscience Institute3533 Southern Boulevard

Kettering, OH

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)

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

Experimental Participants Selected on the Basis of Four Criteria

1) They drink the equivalent of twenty-five drinks per week and are binge drinkers, as opposed to daily drinkers.

2) They have been drinking heavily for more than two years.

3) They do not use other drugs (e.g., marijuana). 4) They do not have significant psychiatric histories

that require the use of medications with potential to affect cognitive function.

Procedure

• PARTICIPANT SCREENINGDay 1:• URINE and BLOOD TESTS• PHYSICAL EXAMINATION• NEUROPSYCHOLOGICAL EXAM• PET SCANDay 2:• URINE and BLOOD TESTS• PET SCAN• MRI SCAN

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?__

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

MRI provides anatomical information

PETMR

Co-Registration Process

Co-Registered

PET scans

SPMmip

[30,

-68,

-44]

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SPM{F1,9

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effects of interest

SPMresults:.\MATLAB\R2006a\work

Height threshold F = 22.86

Extent threshold k = 0 voxels

Design matrix2 4 6 8 10 12

5

10

15

20

contrast(s)

1

z = -46mm z = -44mm z = -42mm F value

0

10

20

30

40

50

60

PET scans

SPMmip

[32,

26,

44]

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< <

SPM{F1,9

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effects of interest

SPMresults:.\MATLAB\R2006a\work

Height threshold F = 22.86

Extent threshold k = 0 voxels

Design matrix2 4 6 8 10 12

5

10

15

20

contrast(s)

1

z = 42mm z = 44mm z = 46mm F value

0

10

20

30

40

PET scans

SPMmip

[-38

, 42,

18]

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SPM{F1,9

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effects of interest

SPMresults:.\MATLAB\R2006a\work

Height threshold F = 22.86

Extent threshold k = 0 voxels

Design matrix2 4 6 8 10 12

5

10

15

20

contrast(s)

1

z = 16mm z = 18mm z = 20mm F value

0

10

20

30

40

SummaryDeficits 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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ReferencesAlfonso-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. Neurosci Biobehav 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.