Cerebral White Matter Effects of Fetal Alcohol Exposure: A Diffusion Tensor Imaging (DTI) Study of Microstructural Brain Abnormalities and Their Neurocognitive Correlates

Jeffrey R. Wozniak, Ph.D.

University of Minnesota

Funded in December, 2005: $100000 for 2 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . FINDINGS . SELECTED PUBLICATIONS .

ABSTRACT

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Cerebral White Matter Effects of Fetal Alcohol Exposure: A Diffusion Tensor Imaging (DTI) Study of Microstructural Brain Abnormalities and Their Neurocognitive Correlates

Prenatal alcohol exposure is the largest single known cause of mental retardation and developmental disabilities in children. Neuroimaging and neuropsychological studies have yielded insights into the underlying effects of alcohol, as well as the resulting cognitive deficits and behavioral symptoms. However, much of the research has focused on children meeting full diagnostic criteria for Fetal Alcohol Syndrome (FAS), who represent 10% or fewer of those affected by prenatal alcohol exposure.

Children with "partial FAS" (pFAS) represent a dramatically understudied group. We will use advanced Magnetic Resonance (MR) imaging methods, including Diffusion Tensor Imaging (DTI), to demonstrate that children with pFAS have abnormalities in brain white matter. We expect to find that these brain abnormalities are correlated with clinical neuropsychological measures, including behavioral inhibition. Because hyperactivity and impulsivity are very common symptoms of fetal alcohol exposure, understanding the brain correlates of these behaviors will be of significant scientific and clinical value.

Unlike conventional MR data, which provides a measure of tissue volume, DTI allows for characterization of tissue integrity at the microstructural level. DTI is particularly well suited to the study of neurodevelopmental disorders such as fetal alcohol exposure because it is sensitive both to  normal developmental changes (such as myelination) and also to insults that occur against that background of normal developmental change in the brain. Because our preliminary data show significant group differences and correlations with behavioral measures, we believe that the proposed imaging methodology is uniquely sensitive to the underlying brain pathology in milder cases of fetal alcohol exposure.

The next steps in this work are to incorporate a wider age range of children (10 to 17 years of age), increase the sample sizes, and add a third group of children with full-criteria Fetal Alcohol Syndrome. We will study 20 patients with pFAS, 20 control subjects, and 10 subjects with full-criteria FAS. All subjects will undergo MRI scans and receive neuropsychological evaluations. We will compare the groups on volumetric measures and on pre-selected regional measures of fractional anisotropy (FA) and mean diffusivity (MD)—both DTI-derived measures of tissue integrity. We will also correlate findings from these DTI measures with neuropsychological and behavioral measures.

This project will contribute significantly to the field because the proposed methodology is state of the art and will yield unique insights into the full range of effects of alcohol on the developing brain.

HYPOTHESIS

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Hypothesis:
1. Children with partial FAS (pFAS) will show abnormalities in white matter microstructure compared to controls.  Children with pFAS will show less severe abnormalities than full-criteria FAS.
2. Children with pFAS will have more severe cognitive and behavioral abnormalities than controls but less severe than full-criteria FAS.  These abnormalities will be correlated with measures of white matter integrity, especially in impulse control and behavioral inhibition.

Goals:
1. The primary goal of the proposed project is to evaluate white matter abnormalities in children with two different degrees of fetal alcohol effects—Full-criteria FAS and partial FAS—by comparing them to control subjects on DTI measures of white matter integrity.
2. A secondary goal of the proposed project is to demonstrate that the white matter abnormalities in patients with FAS and pFAS are related to important neurocognitive and behavioral outcome measures.

The long-term aims of this research are to understand the neurobiological mechanisms that underlie cognitive deficits and behavioral abnormalities in children with fetal alcohol exposure.

Methods:
Each subject will receive a comprehensive neurocognitive evaluation examining.  Subjects will also be seen by a pediatric dysmorphologist, who will take facial measurements and document growth abnormalities (for diagnosing FAS using, the 4-Digit FAS System (Astley & Clarren). We will use the Siemens Trio 3.0 Tesla MRI scanner for imaging.  T1, Turbo SE, Fieldmaps, and DTI sequences are collected.  DTI is 12-direction, processed with FSL, resulting in mean diffusion, fractional anisotropy, radial, and axial diffusivity measures.  We will perform group comparisons and examine correlations between cognitive/behavioral measures and these imaging measures.

FINDINGS

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Lay Results:
The primary goal of this project was to test for developmental brain abnormalities in children who were exposed to alcohol prenatally, by mothers who drank during pregnancy.  Traditionally, the diagnostic procedures have allowed for clear identification of only the most severely affected individuals.  These children with full Fetal Alcohol Syndrome (FAS) have unique facial characteristics and significant intellectual impairments.  A much larger group of children with partial Fetal Alcohol Syndrome (pFAS) has been more difficult to identify.  We utilized a new MRI technique to examine the brains of children with pFAS and FAS.  We also administered a number of cognitive tests in order to understand the relationship between brain abnormalities and actual functional deficits.  The study provides evidence for subtle abnormalities in the white matter (connective networks) of the brains of those children with pFAS and FAS compared to non-exposed children.  Prenatal alcohol is associated with decreased organization of the neural networks in these children’s brains.  This relatively poor organization is associated with deficits in attention and executive functioning skills (planning, organizing, self-monitoring, etc.).  These data help to show that prenatal alcohol exposure is likely associated with brain abnormalities, even in those cases that don’t obviously meet diagnostic criteria for FAS.

Scientific Results:
The primary goal of the proposed project was to evaluate white matter abnormalities in children with two different degrees of fetal alcohol effects—Full-criteria FAS and partial FAS—by comparing them to control subjects on DTI measures of white matter integrity.  A secondary goal was to demonstrate that the white matter abnormalities in patients with FAS and pFAS are related to important neurocognitive and behavioral outcome measures.  DTI scans were collected on a Siemens 3T scanner on 32 children with FASD (23 partial, 9 full FAS) and 21 age and sex-matched controls, ages 10 to 17.  White matter anterior to the genu and inferior to the AC-PC plane was analyzed.  Participants were administered working memory subtests from the WISC-IV or WAIS-III as well as the Wisconsin Card Sorting Test (WCST).  Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Fractional Anisotropy (FA) was lower and Mean Diffusivity (MD) was higher in the FASD group, suggesting less organized white matter in frontal regions.  Within the FASD group, less organized white matter was associated with poor planning and organizing, poor attention shifting, and poor self-monitoring (BRIEF).  White matter abnormality was also associated with poor performance on working memory tasks.  No relationship with the WCST was seen.  Full FAS was associated with more significant white matter abnormality than partial FAS.  In conclusion, DTI revealed frontal white matter abnormalities in children with FASD that are associated with executive functioning deficits reflected in behavior and performance on neurocognitive measures.

SELECTED PUBLICATIONS

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Wozniak J.R., Mueller B.A., Chang P., Muetzel R.L., Caros L., and Lim K.O.  Diffusion tensor imaging in children with fetal alcohol spectrum disorders.  Alcohol Clin Exp Res. 2006 Oct;30(10): 1799-1806.

Wozniak J.R. and Lim K.O.  Advances in white matter imaging: A review of in vivo magnetic resonance methodologies and their applicability to the study of development and aging.  Neurosci Biobehav Rev. 2006;30(6):762-74.