The Effects of Prenatal Alcohol Exposure on Brain and Behavior Edward Riley Center for Behavioral Teratology and Department of Psychology San Diego State.

The Effects of Prenatal Alcohol Exposure on Brain and Behavior

Edward Riley

Center for Behavioral Teratology and Department of Psychology

San Diego State UniversitySan Diego, CA

Alcohol and Pregnancy: An Overview of Fetal Alcohol Spectrum Disorders A Congressional Briefing Sponsored by

The FRIENDS OF NIAAAWednesday, May 20, 2009

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

Facies in Fetal Alcohol Syndrome

Discriminating Features Associated Features

Epicanthal folds

Low nasal bridge

Minor ear anomalies

Micrognathia

Short palpebral fissure

Indistinct philtrum

Thin upper lip

In the young child Streissguth, 1994

Examples of Children with FAS

Short palpebral fissure

Indistinct philtrum

Thin upper lip

*

CNS anomalies

Example of extreme brain damage resulting from prenatal alcohol exposure

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

Small headSmall head

Small noseSmall nose

Small midfaceSmall midface

Long philtrum; Long philtrum; Thin upper lipThin upper lip

normalnormalalcohol-exposedalcohol-exposed

Mouse fetusesMouse fetuses

Comparison: Child with FAS and mouse fetus Comparison: Child with FAS and mouse fetus with fetal alcohol exposurewith fetal alcohol exposure

Child with FASChild with FAS

Short palpebral fissuresShort palpebral fissures

*Photos courtesy of K. Sulik

Critical Periods of Development

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)

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.

0

10

20

30

40

50

60

2001 2002 2003 2004 2005

BingeAny Use

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.

0

2

4

6

8

10

12

14

2001 2002 2003 2004 2005

Binge

Any use

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.

Take Home Message 1

Prenatal exposure to alcohol, at least high doses of alcohol, can cause permanent changes in the brain

Alcohol can act as a behavioral teratogenPrenatal exposure to alcohol can result in a variety

of behavioral dysfunctions, even in the absence of obvious physical effects.

Take Home Message 2

MRI Investigation of Children with FASD

Image Analysis

T1-Weighted Skull stripped tissue segmented Surface rendering

*

Diagnostic Groups

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

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

General Intellectual Performance

NDFASD* * *

IQ scale

FSIQ VIQ PIQ40

55

70

85

100

115S

tan

dar

d s

core

NC

FAS

****

Mattson, S.N., 1997.

FAS is the leadingknown cause ofmental retardation in the western world, but the majority are not retarded

*

Language Test Performance

PPVT-R BNT

30

70

Sta

nd

ard

sco

re

0

10

20

40

50

60

Raw

score

Language Measure

115

130

40

55

85

100

NC

FAS

NDFASD

*

Fine-Motor Skill:Grooved Pegboard Test

Dominant Nondominant

150

Hand

NC

FAS

NDFASD

60

75

90

105

120

135T

ime

(sec

.)

Neuropsychological Performance

FSIQ Read Spell Arith PPVT BNT ATotal VMI PegsD CCT40

50

60

70

80

90

100

110

120

Measure

NC

PEA

FAS

*

Lobe Analysis

*

Frontal Temporal Parietal Occipital0

30000

60000

90000

120000

150000

Vol

ume

Lobe

Controls

FASp = .0003*

p = .018

p = .030

p = .0002*

* Significant after controlling for overall brain size

The parietal lobe is involved in math and visual spatial domains therefore we would expect to

see deficits in these domains

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

problemsHowell, et al (2006) J Ped Psych

Kable and Coles-Fudge, MILE

Streissguth’s cohort

Jacobson and Jacobson

Virtual Water Maze - Probe Trial Paths

Controls FAS PEA*

The frontal lobes, making logical decisions

Role of frontal lobes 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

Frontal Subcortical Circuits

Frontal Cortex

Striatum(caudate & putamen)

Globus Pallidus(part of lenticular nucleus)

Thalamus

Caudate * Accumbens *

70

75

80

85

90

95

100

NDFASD

FAS***

*

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

“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)*

Executive Functioning

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

Cognitive functions involved in planning and guidingbehavior in order to achieve a goal in an efficient manner.

*

Executive FunctioningTower of California Test

Group0

1

2

3

4

5

6

Ru

le V

iola

tio

ns NC

PEA

FAS

Group

8

0

2

4

6

10

Item

s p

asse

d

NC

PEA

FAS

21

3

12

3

Starting position

Ending position

Move only one piece at a timeusing one hand and never place a big piece on top of a little piece

*

Twenty Questions (Concept Formation)

Normal responsesIs it alive?Is it on the left of the

page?Can you eat it?Is it the banana?

The Corpus Callosum

Connects the left and right halves of the brain

Allows them to work together and put information together

Cerebrum

Cerebellum

Corpus Callosum

Corpus callosum abnormalities

Mattson, et al., 1994; Mattson & Riley, 1995; Riley et al., 1995

*

Reductions in Corpus Callosum Area

CON NDFASD FAS

*

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.

DT TRACTOGRAPHYDT TRACTOGRAPHY

13 yr old male control

13 yr old male with FAS

seed volume placed in the splenium of the CC

Combining DTI data withcomputational methods of tractography, the locations and sizes of white matter pathways can be estimated

Left brain/Right brainThe Corpus Callosum

Left Brain

•Language

•Math

•Logic

Right Brain

•Spatial abilities

•Face recognition

•Visual imagery

•Music

What each half of the brain sees

DY

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

What each half of the brain sees

Stimuli

Controls

Alcohol-exposed

Alcohol-exposed

*

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

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

Summary of MRI Findings

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

Prenatal exposure to alcohol, at least in high doses, can cause permanent

changes in the brain 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.

Summary of Neuropsychological Findings

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.

Incidence of FAS in

subsequent births per 1,000 live

births

771

Thank You

Edward Riley

6363 Alvarado Ct. #209

San Diego, CA 92120

[email protected]