We used multimodal neuroimaging to define three fundamental aspects of the brain phenotype in WS that are related to clinical features: 1) Visuospatial construction impairment and adjacent hypofunction in the parietal sulcus region of the dorsal visual processing stream, 2) Hippocampal abnormalities in regional cerebral blood flow, neurofunctional activation, and N-acetyl aspartate concentration, as well as subtle structural changes also contribute to these visuospatial construction problems, and 3) Social cognition features are structural and functional abnormalities in the orbitofrontal cortex. Because these features were defined in extremely rare persons with WS having normal IQs, this allows us to compare WS individuals to IQ-matched healthy controls and thus obviates an important potential confound, these brain phenotypes are likely proximal to the genetic core of the syndrome. We also explored whether the wiring of the human brain is genetically influenced. Here, we used diffusion tensor imaging (DTI) which allows identification of white matter architecture invisible to conventional imaging. This highly uncommon genetic disorder affords a unique opportunity to study genetic regulation of white matter development such as: the regulation of cytoskeletal dynamics in neurons, and neuronal migration and targeting. These participants had been studied with other imaging modalities;therefore our analysis was tailored to specific areas of grey matter structural and functional abnormality. We found that the missing genes confer the unique cognitive and social phenotype of the syndrome by affecting the integrity of long-range, white matter connections between cortical areas, thus affecting the coordination of large ensembles of neurons. Specifically, we showed for the first time that fibers found in white matter immediately underlying gray matter regions previously shown to be abnormal, were oriented differently, gave origin to aberrant posterior tracts, and showed altered lateralization patterns in individuals with WS. We also revealed microscopic alterations of tissue structure. The sample was characterized by the presence of excess longitudinal bundles above the corpus callosum and the absence of an anterior commissure in some WS cases. Given that these genes are missing from the time of conception, this study offered insights into the genetics of neural development, a largely unexplored territory. From these data, we advanced the hypothesis that one or more of the affected genes in WS control development of fibers in the final stages of development and that these fibers, normally growing in a right to left orientation, are deviated longitudinally. This report was the first delineation of white matter structural abnormalities in WS and provided data indicating that the axonal tracts where abnormalities were found may be critically involved in the cognitive and social functions specifically affected in WS subjects. Our observations linked the genes in the microdeleted region of chromosome 7 to the development of long-range connectivity in the brain, and engendered a hypothesis on the mechanism and timing of action of these genes that could guide future investigations in post-mortem tissue and animal models of WS, in particular, and of white matter development, in general. In another study of WS we examined the well characterized hypersocial personality and prominent visuospatial construction impairments, building on our previous findings of functional and structural abnormalities in the hippocampus formation, prefrontal regions, and the dorsal visual stream. The visual stream is divided into two processing steams: a dorsal stream which processes spatial information and a ventral stream which subserves object processing. The hallmark cognitive impairment in WS is in visuospatial construction, the ability to visualize an object (or picture) as a set of parts and construct a replica from those parts. This impairment is characterized neurophysiologically by poor performance on tests of block design or pattern construction. This led to the hypothesis that dorsal, but not the ventral stream function is compromised. Although aberrant ventral stream activation has not been found, object-related visual information that is processed in the ventral stream is a critical source of input into these abnormal regions. This study examined the neural interactions of ventral stream areas in WS using a passive face- and house-viewing fMRI paradigm. During house-viewing, significant activation differences were observed between participants with WS and a matched control group in the brain region, intraparietal sulcus (which processes aspects of the spatial environment). Abnormal functional connectivity was found between the place-processing area (PPA) and parietal cortex, and between face-processing area (FPA) and a network of brain regions including amygdala (fear processing area) and portions of prefrontal cortex. These results indicated that abnormal upstream visual object processing may contribute to the complex cognitive/behavioral phenotype in WS, and provided a systems-level characterization of genetically-mediated abnormalities of neural interactions. We have also employed fMRI-based retinotopic mapping and generated cortical surface models from high-resolution structural MRI to map the size and neuroanatomical changes of the primary visual cortex. Further extending our knowledge of WS visuospatial construction impairments, this year we studied the potential contributions of early visual processing to the cognitive problem. Using fMRI-based retinotopic mapping and cortical surface models from structural MRI, we functionally mapped the size and neuroanatomical variability of the primary visual cortex (V1). We found that V1 did not differ in size between groups, but the anatomical regions were more variable in WS versus controls. Consistent with the notion that neuronal abnormalities subserving visualspatial construction arise later in visual processing, our functional definition of V1 size and location indicates the visual cortex is normal in WS. This is the first functional brain mapping evidence that the earliest cortical visual processing is not impaired in WS.
