A summary of Ann Streissguth's study to measure differences in brain structure caused by prenatal alcohol exposure

[Brain image]
A brain image with landmarks like those
that will be generated by the study.

For more than 20 years fetal alcohol syndrome (FAS) has been recognized as an outcome of prenatal exposure to alcohol. The distinguishing symptoms for diagnosis of FAS consist of a characteristic set of facial anomalies, growth deficiency and brain dysfunction resulting in cognitive and behavioral problems.

Problems related to brain damage are the biggest source of disability from prenatal alcohol exposure and they are not exclusive to FAS. Alcohol is a teratogen that can cause a range of birth defects and affects different people differently. Some individuals whose brains are damaged by exposure to alcohol before birth lack the distinguishing facial anomalies of FAS. They are said to have possible fetal alcohol effects (FAE).

Although the effects of brain damage caused by prenatal exposure to alcohol are plain, their relationship to specific physical anomalies in the brain is not so clear. Many animal studies have demonstrated structural and functional brain impairment as a result of prenatal exposure to alcohol. But, in people with FAS, typical clinical readings of magnetic resonance imaging (MRI) have usually failed to localize brain features that may be only slightly abnormal, yet result in behavior that is clearly the result of brain damage.

A new study led by CHDD research affiliate Dr. Ann Streissguth is designed to elucidate those features. She and her colleagues will be studying the brains and behaviors of individuals with FAS and FAE and comparing them with controls. Using innovative methods of evaluating brain images and specialized neuropsychological testing, their goal is to detect and measure subtle details of brain impairment and tie them to the behavioral problems associated with prenatal exposure to alcohol.

According to Streissguth, professor of psychiatry and behavioral sciences and director of the Fetal Alcohol and Drug Unit, one of the strengths of the five-year study, which is funded by the National Institute on Alcohol Abuse and Alcoholism, is the combined perspectives of researchers from different disciplines-- neuroradiology, statistics and psychology.

The brain images to be used in the study are standard MR images, the same as those commonly used to diagnose brain tumors. The key is in the detailed quantitative analysis, which is different from the clinical reading routinely performed by neuroradiologists. "Radiologists are tuned in to finding areas where there is disease and to finding global measures of volume loss," says Dr. David Haynor, associate professor of radiology, who is in charge of the MRI portion of the study. "Radiologists are not prepared to analyze dozens of features which may be just subtly quantitatively abnormal. They simply can't do that reliably. That's probably why a lot of these clinically read MRIs are normal, because they may be within the gross range of normal, which is a considerable range."

The new method of image analysis was developed by Dr. Fred Bookstein, distinguished research scientist at the University of Michigan, and Dr. Paul Sampson, UW research associate professor of statistics.

"Statisticians use a general method called multivariate analysis to analyze the whole set of different outcome variables or scores that come from complicated measurement systems," explains Bookstein, a consultant on the study. "Over the last few years we have worked out ways of doing a multivariate analysis of a whole picture of a brain with things labeled on it--particular structures or particular points having names. We now have a way of taking this labeled picture of the brain and treating it as a big, complicated piece of data. And, we have figured out how to correlate this complicated piece of data with another complicated piece of data--the profile of performance on a set of neurobehavioral tests--so we can see the extent to which behavior is predicted by structural damage."

With the ability to precisely measure the relative positions of landmark points on the brain, the researchers can detect lack of growth or overgrowth of many important structures. "We take a structure of the brain as defined by a configuration of these named landmarks and compare that configuration, averaged over the sample of patients with FAS, with the same configuration averaged over the control group," says Sampson, who is responsible for data analysis on the study.

Streissguth and Dr. Paul Connor, senior fellow at the Fetal Alcohol and Drug Unit, have designed a battery of tests that will assess study subjects' neuropsychological functioning. The battery addresses specific areas known to be problematic for people with FAS, such as attentional processes and spatial learning. "We've used many of the techniques in the past and found them to be particularly sensitive to prenatal alcohol effects. Also, we are developing some new tests," says Streissguth. "The tests we're using aren't tests that make up a standard neuropsychological battery. Most standard batteries have been developed for people who had an intact brain and then met with an accident or illness. Those tests haven't been as sensitive and discriminating for many people with fetal alcohol effects as the tests we are going to use."

Streissguth is confident that they will be able to recruit the 180 subjects needed for the study. "The sample of patients that we'll be drawing from has been accruing for 23 years here at the Fetal Alcohol and Drug Unit," notes Streissguth. "They have all been seen by a dysmorphologist and been diagnosed with either the full FAS or possible FAE."

Sixty individuals with FAS, 60 with FAE and 60 controls will have MRIs and undergo the battery of neuropsychologic tests. Within each group, half will be adolescents and half adults and, within age groups, half will be male and half female.

"Many of the patients that we've talked with have been quite interested in participating," says Streissguth. "They are interested in how the brain works and how it might work differently as a kind of validation for the experiences they've had." This validation can be especially important for people with FAE.

"People who don't have the facial features are truly discriminated against in terms of services," Streissguth points out. "When they don't have a classic FAS face, the tendency is to act as though there's nothing wrong. They are expected to perform normally, but they're goofing up all the time. They get blamed for being lazy or careless, yet these people have functional brain impairments.

"We find that people with FAS and FAE span a wide range of intellectual functioning. We have many patients that test in the normal range on IQ tests even though they have experienced prenatal brain damage. Because their insult is to the developing brain rather than to the fully developed brain, we don't have an opportunity for a pre-/post- evaluation like we do for people who have brain damage from some trauma, such as head injuries from an automobile accident. After an injury, a person may still function normally on an IQ test, but with areas of deficit. People find that type of brain damage easier to understand because they remember how they were before the auto accident. They knew they were functioning normally then. But people who sustain a prenatal insult to the brain have never had a period of normal functioning."

Correlating specific brain anomalies with specific cognitive and behavioral problems caused by prenatal alcohol exposure could help open doors to services for people with FAE. Such a correlation could also provide a foundation for developing early interventions to ameliorate the effects of prenatal alcohol exposure. The extent of disability for people with FAS or FAE can vary greatly. Currently intervention plans must wait until deficits appear. But if an identifiable variation in the brain form predicts the extent of eventual deficits, it may not be necessary to wait.

"Although this study is only of people 12 and older, you can measure the brain from birth on," explains Bookstein. "The earlier you can find out who is mildly or severely affected, the earlier you can proceed with interventions, with information for parents and with all of the other things we're learning that improve the quality of lives of people with brain damage due to prenatal alcohol exposure."

Study: "Neuroanatomic-Psychologic Analyses of FAS/FAE Deficits" under an NIAAA grant (PI: Dr. Ann P. Streissguth, Fetal Alcohol and Drug Unit, University of Washington; collaborators: Dr. Fred L. Bookstein, University of Michigan, and Dr. David Haynor, Dept of Radiology, University of Washington).

This summary is from an article in the Center on Human Development and Disability's OUTLOOK newsletter (Winter, 1997).

Streissguth's Fetal Alcohol and Drug Unit webpage
Information on FAS disorders