CAPS Research Funding Application Fetal by benbenzhou


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									                                 CAPS Research Funding Application

Scholar Name: Jeffrey Wozniak, Ph.D.          Title: Assistant Professor            Department: Psychiatry

Scholar Signature:
Senior Mentor Name: Kelvin O. Lim, M.D. Senior Mentor Signature:

Title of Project: Cerebral white matter effects of fetal alcohol exposure: A Diffusion Tensor Imaging (DTI)
study of microstructural brain abnormalities and their neurocognitive correlates

1. Prenatal alcohol exposure has been associated with gross structural brain abnormalities, but generally only in
its most extreme form, Fetal Alcohol Syndrome (FAS), which constitutes a minority (10-12%) of the cases. We
hypothesize that the majority of children diagnosed within the broader diagnostic category of Fetal Alcohol
Spectrum Disorders (FASD) have subtle brain damage that will be detectable with DTI. Children with FASD
will have lower fractional anisotropy and higher mean diffusivity than controls in multiple brain regions
including frontal and supra-callosal white matter.

2. We hypothesize that regional abnormalities in white matter integrity, as detected by DTI, will be
correlated with measures of neurocognitive functioning including attention, executive functioning, and
problem-solving – areas of deficit that are commonly seen in children with FASD.

3. The current project will allow us to collect pilot magnetic resonance spectroscopy (MRS) data in order to
characterize neurochemical abnormalities in the brains of children with FASD. We hypothesize that children
with FASD will have a lower NAA:creatine ratio than controls in corpus callosum and basal ganglia.

Specific Aims:
The long-term aims of this research are to understand the neurobiological mechanisms that underlie cognitive
deficits in children with FASD. The proposed project represents a step forward in studying a large sample of
these patients with multiple modalities – incorporating advanced neuroimaging techniques including DTI and
MRS and comprehensive neuropsychological evaluations. This study will:
   Characterize brain abnormalities in an understudied group (children with FASD).
   Relate specific cognitive deficits (ex. attention deficit) to regional microstructural abnormalities.
   Contribute technologically and methodologically to the study of normal and abnormal brain development
    using new techniques that are uniquely suited to the study of the brain during development.

Rationale for Project:
Fetal Alcohol Syndrome (FAS) is the largest single known cause of mental retardation and developmental
disability (Abel, 1995). Recent studies examining the effects of alcohol on brain development have shown that
the associated deficits are not limited to the intellectual domain. In fact, deficits are present in many children
who do not meet the full FAS diagnostic criteria (Mattson et al., 1997). Children exposed to alcohol prenatally
have been found to have a wide range of neurocognitive impairments including deficits in short term memory,
academic skills, sustained attention, fine-motor skill, visual-spatial ability, and executive functioning (Coles et
al., 1991; Janzen, Nanson, & Block, 1995; Mattson et al., 1999; Mattson & Riley, 1998). In addition, alcohol-
exposed children often exhibit severe behavior problems including hyperactivity, impulsivity, and aggression
(Mattson, Schoenfeld, & Riley, 2001). Recent data from 323 children evaluated by the University of
Minnesota’s Fetal Alcohol Clinic show that the majority of children (88%) exposed to alcohol prenatally do not
meet full diagnostic criteria for FAS (Wozniak et al., manuscript submitted for publication). However, our data
clearly demonstrate that these children suffer from many of the same neurocognitive deficits as children who
are diagnosed with FAS. These patients have measurable impairments in attention, memory, learning, and
                                           Wozniak CAPS proposal - 1
higher cognition. Unfortunately, much of the existing research on prenatal alcohol exposure, including much of
the previous neuroimaging work, has focused on FAS. As a result, we know much less about the underlying
neurodevelopmental abnormalities in the larger group of children with FASD.

Methods (one-page maximum):
Subjects: We have ready access to a very well-characterized clinical sample of children with documented
prenatal alcohol exposure through the FASD Clinic directed by Dr. Pi-Nian Chang, housed within the KDWB
University Pediatric Family Center. Patients are drawn from two sources: a database of more than 400 children
already seen in the clinic over the past three years and a steady flow of new patients (approximately 4-5 new
patients are evaluated in clinic per week). We propose to study 20 children with FASD (male and female,
between the ages of 10 and 17).

Procedure: As part of their clinical assessment, each patient receives a comprehensive neurocognitive
evaluation examining intelligence, language skill, attention, memory, learning, motor functioning, and behavior.
This evaluation utilizes standardized neuropsychological instruments including the Wechsler Intelligence Scales
for Children – Third Edition, the Wisconsin Card Sorting Test, and the Scales of Independent Behavior, among
others. Each child is also seen by a pediatric dysmorphologist who takes facial measurements and documents
growth abnormalities (necessary for diagnosing FAS). For this study, diagnoses will be made according to the
most widely used system, the 4-Digit FAS Diagnostic System developed by the University of Washington
(Astley & Clarren, 1997). We will also study 20 age-matched and gender-matched healthy control subjects who
will be administered the same neuropsychological test battery and undergo the same MRI scanning procedures.
        DTI can be used to quantify the magnitude and directionality of tissue water mobility (i.e., self-
diffusion) in three dimensions. Structures in brain white matter, such as myelin sheaths, axon membranes and
cytoskeletal elements act as barriers to water diffusion, causing the water molecules to diffuse farther along
paths that are parallel to fibers rather than paths that are perpendicular to fibers. This directional diffusion is
described as “anisotropic”. Highly regular, organized, healthy fibers have high anisotropy; Underdeveloped,
disorganized, or damaged fibers have low anisotropy. This anisotropy can be quantified and used to assess the
microstructural organization of white matter fibers using the scalar measure fractional anisotropy (FA).
        We will use the 3.0 T Siemens Trio MRI scanner at the University of Minnesota’s Center for Magnetic
Resonance Research (CMRR) to scan our subjects. Staff involved with operating the scanner will be supervised
by Dr. Wozniak and Dr. Lim and will have completed the required CMRR Safety training procedures (SAFE
Magnet, CPR, etc.). Considering subject positioning, scan setup time, scan collection and reconstruction time,
total scanner time will be one hour per subject. The following scans will be collected: a 3 plane localizer, 3D
T1 MPRAGE volume, axial Turbo SE volume, axial 30-direction DTI volume, fieldmap to correct for magnetic
field inhomogeneities, and two operator-positioned single-voxel MRS scans (corpus callosum and basal
        DTI data will be processed using FSL tools including BET, FLIRT, FAST, and FDT. Fractional
anisotropy (FA) is a robust measure that is normalized, and thus appropriate for between-groups comparisons
(Basser, 1995). It represents water molecule diffusion in the direction of white matter fibers. The
physiologically relevant range of anisotropy with FA is 0.2 to 0.8, corresponding to a ratio of about 1:4 between
the largest and smallest diffusivities. A second measure, Mean diffusivity (MD), represents the mean of water
molecule diffusion in all three planes. FA and MD will be derived from FDT calculations. Regions of interest
will be defined in superior frontal, inferior frontal, and supra-callosal white matter in addition to the corpus
callosum itself (anterior, body, and posterior segments). MANOVA will be used to test for group differences in
FA and MD as well as Group x region interactions. Correlations between key neurocognitive variables and FA
and MD will be computed. The Pilot MR spectrosopy data will be processed with in-house software and
exploratory analyses will be carried out using one-way ANOVAs, comparing groups on the NAA:creatine ratio
in the two voxels.

IRB Status: Approved 1/24/2007, Study number 0306M48644.

                                          Wozniak CAPS proposal - 2

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