Sarah N. Mattson - US grants

DESCRIPTION: (Adapted from the APPLICANT'S ABSTRACT) Prenatal alcohol exposure causes a wide range of physical and behavioral effects. The most serious of these is the effect such exposure has on the developing central nervous system and thus the cognitive abilities of the offspring. These deficits often impact the areas of attention, learning, and memory. In general, most assessments of children with FAS, or those who have been prenatally exposed to alcohol, have relied on traditional, fairly global, psychological tests. Recently, however, research has begun to focus on more specific neuropsychological and neuroanatomical measures of alcohol's teratogenicity. For example, deficits in verbal learning with relative sparing in retention of learned material was recently reported in children with FAS. In addition, alcohol-exposed children displayed specific deficits on one measure of visuospatial processing. However, the effects of prenatal alcohol exposure on many of the specific areas of cognitive functioning are unclear. For example, although some evidence exists that spatial memory deficits occur in alcohol-exposed children, little is known about alcohol's teratogenic effect on the visuospatial domain. One aim of this proposal is to evaluate visuospatial functioning in children with histories of heavy prenatal alcohol exposure, using a component-process approach to examine specific aspects of this domain of cognitive functioning. Secondly, recent studies involving magnetic resonance imaging of alcohol-exposed children indicate three brain areas that may be particularly affected. These areas are the basal ganglia, the corpus callosum, and the cerebellar vermis. Behavioral correlates of basal ganglia and corpus callosum abnormalities are currently being assessed but those associated with the cerebellum remain untested in alcohol-exposed children. A second aim of this proposal is to evaluate motor and attentional functioning, which are behaviors known to be associated with the cerebellum. Finally, the specificity of alcohol-related cognitive deficits has not yet been reported. Thus it is unclear whether these deficits are specific to alcohol exposure or are secondary to general cognitive deficits. To address this aim, in both components of this proposal, children with mental deficiency unrelated to prenatal alcohol exposure will be compared to alcohol-exposed children.

The cognitive and behavioral effects of heavy prenatal alcohol exposure are devastating to the individual, their families, educators, and society. However, treatment of these effects remains understudied and many questions remain unanswered. Three decades of research have clearly documented that prenatal alcohol exposure causes cognitive dysfunction. In contrast, little empirical evidence exists on treatment efficacy in this population. Among the most significant of the cognitive effects in these children are those involving attention deficits. Attentional problems are known to respond to treatment in other populations, as in children with attention deficit-hyperactivity disorder (ADHD). About 65 percent of children with ADHD respond to stimulant treatment. Stimulant medication is used with children with histories of prenatal alcohol exposure, but its effectiveness has not been studied empirically. We will evaluate how many children with heavy prenatal alcohol exposure show a positive response to treatment with methylphenidate, a stimulant commonly used in the treatment of ADHD. Effectiveness will be measured using a paired-associate learning paradigm and parent and teacher rating scales. Second, anecdotal evidence suggests that a sizeable minority of alcohol-exposed children will not respond favorably to methylphenidate. At this point, it is not known whether an individual child will be a positive or adverse responder and the pharmacological treatment of these children is often done on a trial-and-error basis. We will assess the ability of neuropsychologic, neuroanatomic, and psychiatric variables to predict either positive or adverse response to methylphenidate in children with heavy prenatal alcohol exposure. Measures of attention/executive function and other neuropsychologic variables, psychiatric diagnosis, family adversity status, and size measures of brain structures affected by heavy prenatal alcohol exposure will be included. Knowledge gained from this research will help to provide a more rational basis for the treatment of the well-documented attentional problems in these children.

DESCRIPTION (provided by applicant): The effects of heavy prenatal alcohol exposure reach beyond the diagnosis of Fetal Alcohol Syndrome and can result in a complex pattern of neurodevelopmental disorders. Although the precise nature of this pattern is not well defined, current research is progressing toward this end. Similarly, brain imaging studies point to a pattern of effects in the brain structure of children with heavy prenatal alcohol exposure with some structures affected to a greater degree than others. The current application proposes studies based on recent neuropsychological and neuroanatomical studies of children with heavy prenatal alcohol exposure. The proposed studies are aimed at clarifying three important functional comparisons: "what" vs. "where" visuospatial processing, "global" vs. "local" hierarchical visuospatial processing, and "disengaging" vs. "shifting" of visual attention. These areas have been linked to the parietal lobe, an area of the brain affected by prenatal alcohol exposure. Although previous studies of individuals with brain damage have assessed these three areas separately, the research proposed herein aims to assess the three domains in one population. First, assessment of "what-where" visuospatial functioning will be conducted using computerized and traditional tests. Based on preliminary data, relative weaknesses in "where" processing are predicted. Second, assessment of global-local processing will be conducted using tests of both recall and potential biasing effects of hierarchical figures. Based on previous research, a relative weakness in local processing is predicted. Finally, assessment of disengaging-shifting of visual attention will be conducted using a classic measure of spatial orienting of attention. Based on both brain imaging studies and previous studies of attentional shifting, a relative weakness in disengagement is predicted. Thus, the proposed series of studies targets three important functional dissociations that are anatomically linked. The underlying rationale and hypotheses for these studies are based on previous neuropsychological and imaging studies. Clarification of these dissociations will help define the profile of weaknesses and strengths in children with heavy prenatal alcohol exposure and help identify core deficits in this population.

DESCRIPTION (provided by applicant): 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.

[unreadable] DESCRIPTION (provided by applicant): This application is part of the competitive renewal for the "Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD)" (Notice RFA-AA-03-004) to continue and expand the current multidisciplinary CIFASD. This RFA calls for, in part, research aimed at "improved diagnosis" and "enhanced understanding of the domains of neurobehavioral impairment" of fetal alcohol spectrum disorders (FASD). Although 30 years of research have identified myriad deficits in individuals with FASD, most neuropsychological studies are plagued by the question of global dysfunction vs. a pattern of relative sparing and impaired function. Delineation of a neuropsychological profile has been the subject of much recent debate. Limited research, including the current CIFASD consortium, has examined if prenatal alcohol exposure results in general dysfunction or a more specific neurobehavioral profile of strengths and weaknesses. The primary aim of this project is to determine whether a neurobehavioral phenotype exists in children with fetal alcohol syndrome, whether the same phenotype exists in children with FASD who lack facial dysmorphology, and whether the phenotype can be used for differential diagnosis. Secondary aims, involving collaboration with other CIFASD projects and cores, are to determine the relationship between brain dysmorphology, facial dysmorphology, and neurobehavioral function. These aims are in keeping with the overall aims of the CIFASD, including enhanced understanding of the neurobehavioral phenotype and establishment of standardized diagnostic criteria and methods of assessment of FASD. A standard neurobehavioral protocol will be administered to four groups of children at six sites and will address the functional domains of executive function, working memory, verbal function, and psychological symptomatology. In addition to children with FASD and nonexposed controls, children with low IQ scores or ADHD will be included as contrast samples. Using this heterogeneous sample and multivariate statistical methods, neurobehavioral profile specific to FASD will be sought. In addition, participants will be assessed using methodology prescribed by the Dysmorphology Core and the facial and brain imaging projects of the CIFASD. Data from three broad domains (neurobehavior, dysmorphology, and brain morphology and function) will be analyzed both separately and together to address the main aim of the CIFASD: improving the diagnostic criteria for FASD. This project is directly relevant to public health concerns surrounding the effects of heavy prenatal alcohol exposure, improving diagnosis of alcohol-affected individuals, and defining the profile of neurobehavioral effects that are specific to FASD. Improved identification and delineation of these features will ultimately lead to improved treatment. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The effects of heavy prenatal alcohol exposure reach beyond the diagnosis of Fetal Alcohol Syndrome and can result in a complex pattern of neurodevelopmental disorders. Although the precise nature of this pattern is not well defined, current research is progressing toward this end. Similarly, brain imaging studies point to a pattern of effects in the brain structure of children with heavy prenatal alcohol exposure with some structures affected to a greater degree than others. The current application proposes studies based on recent neuropsychological and neuroanatomical studies of children with heavy prenatal alcohol exposure. The proposed studies are aimed at clarifying three important functional comparisons: "what" vs. "where" visuospatial processing, "global" vs. "local" hierarchical visuospatial processing, and "disengaging" vs. "shifting" of visual attention. These areas have been linked to the parietal lobe, an area of the brain affected by prenatal alcohol exposure. Although previous studies of individuals with brain damage have assessed these three areas separately, the research proposed herein aims to assess the three domains in one population. First, assessment of "what-where" visuospatial functioning will be conducted using computerized and traditional tests. Based on preliminary data, relative weaknesses in "where" processing are predicted. Second, assessment of global-local processing will be conducted using tests of both recall and potential biasing effects of hierarchical figures. Based on previous research, a relative weakness in local processing is predicted. Finally, assessment of disengaging-shifting of visual attention will be conducted using a classic measure of spatial orienting of attention. Based on both brain imaging studies and previous studies of attentional shifting, a relative weakness in disengagement is predicted. Thus, the proposed series of studies targets three important functional dissociations that are anatomically linked. The underlying rationale and hypotheses for these studies are based on previous neuropsychological and imaging studies. Clarification of these dissociations will help define the profile of weaknesses and strengths in children with heavy prenatal alcohol exposure and help identify core deficits in this population.