Research Projects: Phase I Projects

  • Phillip May
    International Neuropsychological Study of FASD
  • Ed Riley
    A Cross-Cultural Assessment of FASD Administrative Core; Pilot Project Core – CIFASD; Neurobehavioral Core for CIFASD

 

Risk Factors for FASD in the Moscow Region

Christina Chambers, Principal Investigator/Program Director

Defining the range of expression, risk factors for, and incidence of FASD in children born to women who drink varying amounts of alcohol during pregnancy is of vital importance in terms of prevention, intervention and treatment. The proposed study entails a collaboration with the Moscow Region Ministry of Health to screen 26,000 pregnant women over two years. From these, 640 moderate to heavy drinkers and 640 controls will be selected for longitudinal follow-up including standardized physical exams and neurobehavioral testing of infants through twelve months of age. The specific aims of the project are: 1) To measure the birth prevalence and range of alcohol-related physical features and neurobehavioral impairment among children born to pregnant women in the Moscow Region who report consuming moderate to heavy amounts of alcohol by utilizing methods designed to permit earlier diagnosis of alcohol-related effects, and 2) To evaluate the contribution of maternal nutritional factors to increased risk for prenatal growth deficiency, neurobehavioral impairment, and alcohol-related physical features In infants prenatally exposed to moderate to heavy amounts of alcohol by conducting a randomized trial of a micronutrient supplementation intervention and measuring micronutrient levels in maternal blood. The proposed study will contribute to a better understanding of the Incidence and range of FASD based on early diagnosis in a cross-cultural environment, and will for the first time specifically test a nutritional intervention that may have widespread applicability should under-nutrition prove to be a modifiable risk factor for FASD.

A Cross-Cultural Longitudinal Assessment of FASD

Tatiana Foroud, Program Director/Principal Investigator

It has been demonstrated that anthropometric data can accurately distinguish individuals with Fetal alcohol syndrome (FAS) from those who were alcohol exposed but do not manifest the full spectrum of clinical features, and those who were not alcohol exposed [2]. A more efficient means to collect such data may be through three-dimensional (3.D) digitizing instruments, which can capture a facial image that can then be used to collect a wide range of known and novel clinical variables. Through the collection of 3-D images from individuals of variable ethnicity, age and exposure histories, it should be possible to identify a series of variables that effectively discriminate individuals who were prenatally exposed to alcohol and the degree to which they were exposed, from those who were not exposed.

The goal of this collaboration is to analyze three-dimensional (3-D) facial images from individuals of variable ethnicity, age and history of alcohol exposure. The analyses of 3-D facial imaging will be developed and utilized for more effective clinical diagnosis of FAS, as well as the more broadly defined FASD. In addition, we believe these studies will generate important insight regarding the changes that occur in the face both prenatally and postnatally that produce the clinical features associated with FAS and thereby provide improved understanding of the pathophysiological effects of ethanol on human development.

To accomplish these goals we propose the following specific aims: 1) Train and supervise personnel at each recruitment site to ensure collection of standardized data; 2) Analyze the 3-D facial imaging data to identify the measurements that most efficiently differentiate alcohol exposed from control subjects; 3) Utilize algorithms and methods derived from the emerging field of Automated Facial Recognition (AFR) to extract and identify the most discriminating higher order surface features from 3-D facial images, with the goal of developing an automated method of identifying facial features diagnostic of prenatal alcohol exposure; and 4) Combine the results from the direct and higher order measurements derived from the 3-D facial imaging with variables collected from other study domains to improve the power to accurately discriminate alcohol exposed from control subjects and to better understand the pathophysiological effects of ethanol on human development.

Testing FASD Therapeutic Agents: Neonatal Rodents Models

Charles R.Goodlett, Principal Investigator/Program Director

The long-term goals of this component are to use rodent models of binge alcohol exposure during the 3rd trimester equivalent to screen and identify molecular agents that may be effective in preventing prenatal alcohol-induced brain damage and neurodevelopmental disorders. These studies will use two neonatal rodent models. The first is the well-studied model involving binge alcohol exposure on postnatal days (PD) 4-9 in outbred rats, which is known to produce structural and functional damage to cerebellar systems. The second is a model involving a single binge alcohol exposure on PD7 in the C57BL/6 inbred mouse strain (the focus of Zhou’s mouse component), known to induce extensive forebrain neuronal cell death. These studies will assess the effectiveness of candidate therapeutic agents by evaluating alcohol-induced damage to cerebellar (rat) and hippocampal (mouse) circuits that are known to mediate specific variants of Pavlovian eyeblink classical conditioning (ECC). In keeping with the emphasis of the Core, L-NAP, a 9-amino acid derivative of activity-dependent neuroprotective protein, will be the first candidate agent tested, because of its demonstrated effectiveness in several models of cell death and in a mouse model alcohol induced teratogenesis. If L-NAP is found to be effective, additional studies of two structural derivatives of L-NAP for which the capacity to protect against neuronal death vs. ethanol teratogenesis has been dissociated, will also be evaluated. Specific Aim 1 tests the hypothesis that the candidate agent will protect against alcohol-induced caspase-3 activation on PD 4 in Purkinje cells, an indicator of acute Purkinje cell death. Specific Aim 2 tests the hypothesis that the candidate agent will protect against functional and structural damage to cerebellar systems mediating eyeblink conditioning induced by binge alcohol exposure on PD 4-9. Specific Aim 3 tests the hypothesis that binge alcohol exposure on PD 7 in C57BL/6 mice will damage hippocampal circuits necessary for eyeblink discrimination reversal learning, and that the candidate agent will protect against this hippocampal damage. Because the neural substrates and procedures for ECC are similar across species, the outcomes from these animal models including those of the sheep model component of this Consortium can be translated directly to humans to guide and inform future studies of therapeutic prevention of FASD. A key advantage of integrated approaches across the Consortium is that as promising candidate molecular agents emerge, these animal models can provide in vivo tests of their therapeutic effectiveness.

Testing FASD Therapeutic Agents in C57/BL Mouse Model

Feng C. Zhou, Investigator

Maternal alcohol consumption is the leading known cause of mental retardation in the Western world. The fetal alcohol spectrum disorder (FASD) including fetal alcohol syndrome and alcohol-related neurodevelopmental disorder causes a life-time disability to the victim. The goal of this project is to test therapeutic agents that can protect against FASD, particularly the central nervous system. The activity dependent trophic factor and their associated peptides has been known to be extremely potent as protectant against oxidative stress and alcohol induced fetal demise.

The goals of this project will be to (a) test the protective/neurotrophic effects of ADNF-like peptides against alcohol compromised neurons, particularly the serotonin, and excitatory neurons in the limbic system. Due to extremely dynamic change in neural development, the effect of ADNF-like peptides will be tested against alcohol exposure at pre- and neo-natal stages of mice equivalent to the human lst/2nd and 3rd trimesters respectively. (b) Second, we will study the mechanism of ADNF-like peptide protection by analyzing its gene expression in a selective paradigm.

The Aim 1 will test the neuroprotective and/or neurotrophic effect of ADNF-like peptides against alcohol neurotoxicity to developing serotonin (5-HT) and hippocampal neurons by study their apoptosis, number of matured neurons, and degree of 5-HT and glutamate innervation in the hippocampus with an established alcohol liquid diet model at E7- E18, equivalent to 1st and 2nd trimesters of human gestation. The Aim 2 will determine the neuroprotective and neurotrophic effect of ADN F-like peptide on an alcohol induced apoptosis, neurogenesis, synaptogenesis of the limbic system with binge ethanol exposure at a neonatal stage equivalent to 3rd trimester of human gestation. The Aim 3 will analyze the mechanism of ethanol neurotoxicity in the neonatal binge alcohol exposure model, and the protective effects of ADNF-like peptide upon gene expression, for understanding toxicity and protection, using microarray analysis, real-time RT-PCR and in situ hybridization.

Identification of FASD in South African Children

Sandra W. Jacobson, Principal Investigator/Program Director

Early identification of children with FASD has been limited by the difficulty of reliably evaluating facial dysmorphology and because investigators have not yet identified a set of neurobehavioral deficits specifically related to prenatal alcohol exposure. However, a new generation of neurodevelopmental measures that have been linked more specifically to neural processes and pathways has the potential to improve FASD diagnosis. We have recently completed a prospective study of 159 infants born to mothers from the Cape Coloured (mixed race) community in South Africa, which has confirmed the exceptionally high incidence of maternal alcohol abuse and dependence and FAS previously documented in this population. Arithmetic and executive function (EF) are among the most consistently affected domains in older children with FASD. In our Cape Town cohort, we were able to detect deficits in these domains in infancy using two innovative infant assessments: a numerosity test, which assesses magnitude representation, a precursor of arithmetic that has been linked to inferior parietal function, and the A-not-B test, an early precursor of EF. New data from our Detroit prenatal alcohol exposure cohort also provide evidence of a specific deficit in magnitude representation in older children and poorer conflict monitoring, an aspect of EF believed to be mediated by the anterior cingulate cortex.

This component of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) will follow up our Cape Town cohort at 4 and 6 years of age. The specific aims are: (1) to administer new narrowband tests of arithmetic and EF to determine which elements of these domains appear to be core deficits of FASD, (2) to administer event-related potential (ERP) assessments of magnitude representation and recognition of facial emotional expression, two domains that are hypothesized to relate specifically to FASD; (3) to test the hypothesis that two moderator variables – maternal age and the absence of an ADH22 allele – can improve the identification of FASD in prenatally exposed children; (4) to assess the predictive validity of infant numerosity and A-not-B in relation to cognition and attention in early childhood; (5) to determine the degree to which measures of craniofacial variation derived from 3-D photography can improve FASD diagnosis; and (6) to administer additional neurobehavioral assessments in common with other CIFASD projects to provide data on the sequelae of FASD that can be pooled and compared across age, site and ethnic group. Improvement of diagnosis in infancy and early childhood and a better understanding of the specific domains of neurobehavioral function affected by fetal alcohol exposure are critically important for the development and implementation of targeted, effective interventions for FASD.

Dysmorphology Core

Kenneth Lyons Jones, Principal Investigator/Program Director

Diagnosis of the Fetal Alcohol Spectrum Disorder (FASD) is dependent on the identification of a pattern of malformation including alterations in growth and neurobehavioral development as well as a constellation of specific minor craniofacial anomalies. In that a neurobehavioral phenotype specific for prenatal alcohol exposure has not yet been identified, it is presently not possible to diagnose FASD in the absence of the clinical phenotype. It will be the responsibility of the Dysmorphology Core to assure accurate and consistent diagnosis of FASD in children at all consortium sites through implementation of a standard protocol based on documentation of the clinical phenotype which will be used at all sites. In that this consortium will integrate investigators from different sites throughout the world, it is imperative to have a small core of individuals with extensive experience in evaluation of children prenatally exposed to alcohol responsible for diagnosis of FASD at all sites.

Identification of large numbers of children with FASD at various ages, each of whom has received a standardized clinical evaluation will provide the opportunity to gain new insight into a variety of issues relating to the clinical phenotype including the full range of structural defects in the disorder, physical features that are predictive of alterations in neurobehavioral development, the extent to which degrees of growth deficiency should be used to enhance specificity of diagnosis without loss of sensitivity, and will provide the opportunity to develop strategies to diagnose this disorder in the newborn period.

FASD in San Diego and Moscow

Sarah Mattson, Principal Investigator/Program Director

The current proposal is in response to RFA-AA-03-002 and is part of the consortium application, entitled “Cross-Cultural Assessment of FASD.” This RFA calls for, in part, “research to better define and characterize the description of FASD” including identification of core deficits in this population. The current application meets this goal by proposing research aimed at identifying core neuropsychological and neuroanatomical features in children with fetal alcohol syndrome and fetal alcohol spectrum disorder (FASD) in two samples of children in two countries, the United States and Russia.

Thirty years of research and practice have confirmed that (1) alcohol is a teratogen, (2) the brain is the organ most sensitive to alcohol’s effects, and (3) the effects are of a continuous nature. Questions that remain pertain to whether a profile of core deficits and strengths exists, what this profile tells us about the underlying function of the brain, and whether effects can be accounted for by other environmental circumstances like living environment or general intellectual functioning. The current proposal includes both neuropsychological and brain imaging studies and is aimed at characterizing an FASD phenotype. Importantly, two distinct populations will be assessed, children in San Diego, California, and children in Moscow, Russia. The inclusion of these two populations will allow us to answer important questions relating to the role of environment, culture, and general intellectual functioning in the phenotype of FASD. Children in Moscow will primarily be ascertained from boarding schools and orphanages that house children with subnormal intellectual functioning. We have previously determined the rates of FAS in this population are very high. Children in San Diego will be ascertained from ongoing studies of FASD at the SDSU Center for Behavioral Teratology. Thus, we have the unique opportunity to examine the relationship between FASD, IQ, and living environment in large groups of children.

In addition to the unique aspects mentioned above, the current application dovetails with other applications in the consortium, allowing large groups of children with FASD to be examined in several international sites using consistent measures. The opportunity for convergence of data from these multiple sites provides tremendous power to test specific hypotheses regarding the phenotype of FASD.

Neurobehavioral Outcome in Adolescents with FAS & FASD

Ilona Autti-Ramo, Investigator

The present proposal outlines a research project to be conducted on adolescents and young adults that have earlier been assigned diagnoses of Fetal Alcohol Syndrome (FAS) or Fetal Alcohol Spectrum Disorders (FASD). The general aim is to study the status in adolescence of these persons on many levels: educational and societal, cognitive and behavioral, as well as neurobiological. The first specific aim is to evaluate long-term outcome for FAS/FASD in Finland. Using questionnaires and in-depth interviews the education and professional activities as well as social functioning and mental well-being of the study group is reviewed. High rates of secondary disabilities have been reported for young adults with FAS/FASD in the United States. It is of interest to see whether the same difficulties appear in other cultures. Specifically, it would be of interest to know to what extent the secondary disabilities are influenced by the social context in which the children with FAS grow up. The second specific aim is to assess the neurocognitive profile of the FAS/FASD subjects. We intend to perform a comprehensive assessment of neurocognitive abilities, including attention and executive functioning, language, visual perception, motor functioning as well as memory and learning. The importance of a broad neuropsychological assessment has been stressed by us and by others since prenatal alcohol prenatal alcohol may affect many areas of neuropsychological functioning. The third specific aim is to obtain further information concerning the neurobiological pathology and structural abnormalities underlying impairments specific to FAS/FASD. Magnetic resonance spectroscopy (MRS) is carried out in order to study whether possible brain anatomic and metabolic deviance may underlie characteristic impairments of FAS/FASD. Results are compared with neuropsychological findings. Furthermore, Magnetic Resonance Imaging (MRI) is carried out in order to gather more understanding of the vulnerability of structural brain development during pregnancy.

International Neuropsychological Study of FASD

Phillip May, Principal Investigator/Program Director

This work focuses on high risk samples that are likely to contain more individuals at the extreme end of the spectrum of outcomes for FASD. The PI critically reviews the literature on neuropsychological features of FASD children and points out that the primary finding is reduced intellectual ability, as opposed to a specific profile of strengths and weaknesses. He argues that this is reflected in good performance on simpler tasks and weaker performance on more complex, integrative tasks that cut across domains. This is interpreted in the context of a ‘g factor’or ‘radex’ model. Inherent in the review is an emphasis on the importance of factors such as symptom severity (FAS vs. FAE)/dysmorphology as possible correlates of marked neuropsychological compromise and the suggestion that benefit is to be derived from first trying to identify a behavioral phenotype among the severely affected before trying to extend it the milder FASD outcomes. The proposed work examines the neuropsychological and other features of more severely affected individuals in certain South African and Native American groups.

Multi-Method Intervention Study of FASD in South Africa

Piyadasa Kodituwakku, Investigator

Despite ongoing efforts to prevent maternal drinking during pregnancy, prenatal alcohol exposure continues to be the leading non-genetic cause of mental retardation. As the result of ongoing epidemiological studies in South Africa since 1 999; the prevalence of fetal alcohol syndrome (FAS) in the western Cape Region of South Africa has been found to range from 48 per 1000 to 75 per thousand among school children ages 5 to 9 years. Those are the highest recorded rates in any general community in the world and are many times higher than prevalence estimates for the United States. Even though the need for developing intervention programs for alcohol-affected children has long been recognized, no systematic outcome studies of such intervention programs exist. Therefore, file current project aims to test the efficacy of three intervention methods in the remediation of specific behavioral and learning problems in alcohol-affected children in the Western Cape Province of South Africa. The specific aims of the multi-method study are: 1) To determine the degree to which cognitive control therapy improves academic skills and behavior in alcohol-exposed children; 2) To determine the degree to which family interventions Improve academic skills and behavior of alcohol-exposed children: 3) To determine the degree to which specific linguistic and literacy training programs Improve academic skills and behavior of alcohol-exposed children: 4) To determine the degree to which environmental modifications in the classroom (e.g. limited class size and structured teaching) improve academic skills and behavior in alcohol-exposed children; 5) To determine the degree to which combinations of above methods improve academic skills and behavior in alcohol-exposed children; 5) To assess the effects of 3 mediating variables (self efficacy, attention, meta-cognitive skills) and 3 moderating variables (child’s IQ, life stress, maternal education) on therapeutic outcomes.

One hundred and twenty children, ages 7 to 9 will be recruited through an epidemiological study currently being conducted in the Western Region of South Africa. Twenty children will be randomly assigned to one of six groups, four treatment groups (cognitive control therapy, family support. classroom modification, and linguistic and literacy training) and one alcohol-exposed control group and one typically developing control group. During the first phase of the project, all treatment and control-group children will be administered a comprehensive battery of tests consisting of a neuropsychological test battery, tests of academic achievement, selected speech/language tests, and a functional behavior assessment. The pre-testing will serve the following two distinct purposes: 1) to provide pretest data for each child in the research cohort and, 2) to identify current educational and: behavioral issues for each child in the study. Following the pre-testing, each of the three proposed intervention methods will be administered once a week with children in each study group over a period of 18 months. In addition each child in the study will be observed by a blinded observer 4 times in the prescribed lime of intervention. After the 18- month intervention trial, the same testing battery will be administered as post intervention measures. The pre-test and post-test performance of the children will be analyzed.

Photolabeling of Alcohol Binding Sites

Keith W. Miller, Principal Investigator/Program Director

Our overall hypothesis is that ethanol-induced inhibition of cell adhesion, one possible cause of damage in the developing neural system, is mediated by alcohol binding sites on the Li cell adhesion molecule. Different alcohols show remarkable structural specificity for alcohol inhibition of cell adhesion (agonist action). Other alcohols (e.g., 1-octanol) noncompetitively antagonize the effects of ethanol on LI-mediated cell adhesion and on the development of mouse whole embryo cultures. We hypothesize that these sites are on Li because the brains of children with Li mutations resemble those of children with fetal alcohol spectrum disorder (FASD). The novel aspects of this proposal is the use of recently developed photo affinity alcohol analogs, 3-azibutanol (an agonist) and 3-azioctanol (an antagonist) to photo label the agonist and antagonist binding sites respectively. Specific Aim 1 tests the hypothesis that there are alcohol agonist sites on the Li adhesion molecule by photolabeling them with 3-azibutanol, which acts similarly to ethanol on cell adhesion. Purified Li photo labeled with [3H13-azibutanol will be digested and fragments photo incorporating alcohol separated by H PLC. The stoichiometry of photo incorporation will be measured by mass spectrometry. Further, digestion of target fragments will produce fragments suitable for sequencing by mass spectrometry. To assess pharmacological relevance, the apparent dissociation constant and pharmacology of each photoincorporation site will be determined and compared to those obtained from parallel cell adhesion experiments. Specific Aim 2 similarly tests the hypothesis that there are separate alcohol antagonist sites on Li using the photoaffinity label, 3-azioctanol, which inhibits ethanol-induced inhibition of cell adhesion at micromolar concentrations. We expect to define at least one amino acid in the binding pocket of each pharmacologically well-characterized site on LI. Identification of the agonist and of the antagonist site will, respectively, aid in understanding the molecular basis for FASD and accelerate the development of drugs that block the toxic effects of ethanol on the developing nervous system.

Ed Riley, Principal Investigator/Program Director

A Cross-Cultural Assessment of FASAD Administrative Core

The purpose of this application is to develop a Consortium for the “Collaborative Initiative on Fetal Alcohol Spectrum Disorders” (CIFASD). The CIFASD will coordinate basic, behavioral, and clinical investigators in a multidisciplinary research project to better inform approaches aimed at developing effective intervention and treatment approaches for FASD. It will involve the input and contributions from basic researchers, behavioral scientists, and clinical investigators with the willingness to utilize novel and cutting edge techniques, not to simply replicate previous or ongoing work, but rather to move the field forward in a rigorous fashion. The first step is to definitively outline a diagnostic schema so that the full range of effects from prenatal exposure to large or moderate amounts of alcohol can be determined. While an abundance of evidence exists on the outcomes following prenatal alcohol exposure, one of the hindrances to developing a full set of criteria for diagnosing FASD has been the lack of adequate numbers of subjects at any single research site. This consortium will integrate researchers from a number of sites, including several international locations, to share common protocols, so that a large number of individuals can be assessed using similar procedures. These sites will interface with cores providing expertise in dysmorphology, behavioral assessment, and brain imaging. We will integrate the data collected at the various sites in the various domains (dysmorphology, behavior, brain) to develop a comprehensive assessment battery. At the same time, we will develop state of the art methodology to better define the diagnosis and the full range of effects resulting from prenatal alcohol exposure. This consortium will also include basic science components, whose long-range goals are aimed at developing effective interventions. The basic science components will inform the clinical components and vice versa. All projects and cores will interface with the Administrative Core and the Informatics Core to provide for the flow of information between the various PIs involved in this consortium. The purpose of this consortium is to provide the answers to much needed questions as it relates to the full spectrum of consequences resulting from prenatal alcohol.

Pilot Project Core – CIFASD

The Pilot Project Core provides one mechanism by which this consortium acts as a dynamic entity. It provides a flexible means for developing and exploring new research activities and directions for the Consortium and a mechanism by which new sites can be added or projects can evolve into independently funded research projects. During the 5 years of this Consortium we believe that we can fund approximately 14 pilot projects. We will start with 4 pilot projects in the 01-year, each running for two years. New projects will start as these end, some will be funded for a single year and others for two years. Of course other projects might be phased in as a funded pilot project spins off early into a regular research projects, or the progress on a pilot project is such that it is terminated early. The Consortium Coordinator will manage the Pilot Project Core, although again the Steering Committee will be intimately involved in this process. Following the initial round of pilot projects, additional projects will be solicited from Consortium members, affiliated investigators, other scientists interested in FASD, and investigators from others areas who might be interested in becoming part of the consortium. Announcements of the availability of these projects will be made through the Fetal Alcohol Study Group of the RSA, and other professional outlets. Each application for a pilot project will be screened by at least two members of the Scientific Advisory Board for scientific merit, innovation, and relationship to other projects in the Consortium. Applications that pass this first screen will be sent to the Steering Committee, which will assign primary and secondary reviewers of each proposal. These proposals will be discussed at one of the two annual meetings of the group. Pilot projects for the initial term were chosen with new ideas in mind. There was an emphasis on adding new sites that might contribute to the overall functioning of the Consortium over the long-term. These sites would have unique resources available to them, or unique attributes about the population under study. Thus, projects were chosen to be conducted in Buffalo, NY; the Ukraine; and Rome, Italy. The other consideration was that the pilot projects should utilize new and novel methods to assist in the diagnosis or treatment of FASD. In this regard, a project was chosen with a potential of diagnosing FASD early in life, based upon ultrasound imaging of the corpus callosum.

Neurobehavioral Core for CIFASD

The purpose of the Neurobehavioral Core is to provide for the assessment of the behavioral manifestations of fetal alcohol spectrum disorder (FASD) in order to provide a valid profile or profiles that would be useful in detecting prenatal alcohol effects. Since previous research suggests that there is a wide range of neurobehavioral outcomes, the core must be sensitive to the impact of prenatal exposure on cognitive, emotional and social functioning as it is manifest throughout infancy, childhood, into adulthood. The responsibilities of the Core will include: 1) Specification of an appropriate and flexible test battery that can be used by the Collaborative project sites to assess alcohol exposed individuals from birth into adulthood. The purpose of this aim is to be able to suggest a battery of tests capable of detecting prenatal alcohol exposure even in nondysmporphic individuals. 2) Support the various research sites with test and test materials. 3) To assist in the identification of the appropriate control factors that should be collected at all sites and to assist in determining what measures should be used in the collection of this information. 4) Respond to issues of training in the administration of these measures and to provide quality control over the assessments. 5) Establish and maintaining an interactive database of test outcomes and to interact fully with the Informatics Core to make these data available. 6) To interact with the Dysmorphology, Brain Imaging, 3D Facial Imaging, and Informatics Cores to determine the relationships between the various measures.

A Cross-Cultural FASD: Brain Imaging

Elizabeth Sowell, Program Director/Principal Investigator

The overarching goal of this proposed Imaging Core is to understand better the effects of prenatal alcohol exposure on the structure and function of the developing brain by facilitating the use of advanced brain image processing tools by CIFASD members. One of the key limitations in understanding the role of severe prenatal alcohol exposure on the developing brain has been the limited number of subjects studied by any single research group. It is our intent to use this opportunity to pool structural brain imaging data across multiple research sites by standardizing the imaging protocols used to acquire image data, and standardizing image analysis tools used to compare individuals with fetal alcohol spectrum disorders (FASD) to controls. We will use our expertise to provide members of the Consortium with access to relatively simple automated image analysis tools that they can use in their laboratories to assess the shape and size of the corpus callosum (CC) and other regularly shaped brain structures. More specialized tools will be developed to assess differences in brain morphology in cortical and subcortical structures and to combine functional and structural MRI data for within-project functional-structural MRI studies. Specifically, our efforts will be directed towards: 1) the standardization of image acquisition protocols and validation of methods for controlling scanner specific geometric distortion through the use of human and mechanical phantom studies; 2) the adaptation of automated image analysis tools for distribution to CIFASD members; 3) adaptation and creation of more sophisticated tools for assessment of brain shape and tissue distribution abnormalities in cortical and subcortical regions, and the refinement of tools designed to facilitate the combination of functional and structural brain imaging data; and 4) the assessment of relationships between brain image data, and data collected by the other CIFASD projects and cores. Consortium members are proposing to collect either functional or structural (or both) brain imaging data from over 470 children and adolescents with FASD and 310 control subjects. The strategies and methods developed within the Imaging Core will for the first time allow the direct comparison of data collected at various sites, dramatically increasing our power to potentially outline diagnostic criteria from brain imaging data, and ultimately to help develop intervention and treatment approaches for FASD.

Informatics Core for the Collaborative Initiative on FASD

Craig A. Stewart, Principal Investigator/Program Director

he Informatics Core is part of the Consortium for the “Collaborative Initiative on Fetal Alcohol Spectrum Disorders” (CIFASD). The theme of this collaborative initiative is a cross-cultural assessment of “fetal alcohol spectrum disorder” (FASD). The CIFASD will coordinate basic, behavioral, and clinical investigators in a multidisciplinary research project to better inform approaches aimed at developing effective intervention and treatment approaches for FASD. It will involve the input and contributions from basic researchers, behavioral scientists, and clinical investigators with the willingness to utilize novel and cutting-edge techniques so as not to simply replicate previous or ongoing work, but rather to try and move it forward in a rigorous fashion.

The Informatics Core will develop and maintain the CIFASD Data Repository, which will be used to collect, maintain and distribute data generated by the various participants in the consortium. The Informatics Core will be responsible for working with the other consortium participants to define a Data Dictionary to be used in standardizing data collection, enabling the transfer of data to and from the CIFASD Data Repository, consulting on how to establish local data management systems, providing both software tools and consulting to consortium participants, and producing status reports about the progress of the various projects within the consortium.

The Informatics Core draws on a wealth of resources, experience, and expertise at Indiana University in information technology infrastructure and data management, The CIFASD Data Repository will be developed on Indiana University’s state-of-the-art central supercomputing facilities, taking advantage of Indiana University’s strong commitment to institutional computational resources. Resources that will be used to implement the CIFASD Data Repository include multiple supercomputers, an array of readily available database and statistical software, and a high-speed, secure, robust data archiving system capable of storing duplicate copies in multiple physical locations separated by more than fifty miles.

The Informatics Core will use these extraordinary computational resources to provide a single, highly secure location for consortium participants to obtain the cross-cultural data that will enable the CIFASD to meet its goals of developing novel techniques for intervention and treatment of FASD.

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