Ursula Bellugi

I. The Neurocognitive Profile of Williams Syndrome: A Complex Pattern of Strengths and Weaknesses

The rare, genetically based disorder, Williams syndrome (WMS), produces a constellation of distinctive cognitive, neuroanatomical, and electrophysiological features which we explore through the series of studies reported here. In this paper, we focus primarily on the cognitive characteristics of WMS and begin to forge links among these characteristics, the brain, and the genetic basis of the disorder. The distinctive cognitive profile of individuals with WMS includes relative strengths in language and facial processing and profound impairment in spatial cognition. The cognitive profile of abilities, including what is typical for individuals with WMS is discussed, but we also highlight areas of variability across the group of individuals with WMS that we have studied. Although the overall cognitive abilities (IQs) of individuals with WMS are typically in the mild-to-moderate range of mental retardation, the peaks and valleys within different cognitive domains make this syndrome especially intriguing to study across levels. Understanding the brain basis (and ultimately the genetic basis) for higher cognitive functioning is the goal we have begun to undertake with this line of interdisciplinary research.

II. Hypersociability in Williams Syndrome

Studies of abnormal populations provide a rare opportunity for examining relationships between cognition, genotype and brain neurobiology, permitting comparisons across these different levels of analysis. In our studies, we investigate individuals with a rare, genetically based disorder called Williams syndrome (WMS) to draw links among these levels. A critical component of such a cross-domain undertaking is the clear delineation of the phenotype of the disorder in question. Of special interest in this paper is a relatively unexplored unusual social phenotype in WMS that includes an overfriendly and engaging personality. Four studies measuring distinct aspects of hypersocial behavior in WMS are presented, each probing specific aspects in WMS infants, toddlers, school age children, and adults. The abnormal profile of excessively social behavior represents an important component of the phenotype that may distinguish WMS from other developmental disorders. Furthermore, the studies show that the profile is observed across a wide range of ages, and emerges consistently across multiple experimental paradigms. These studies of hypersocial behavior in WMS promise to provide the ground-work for crossdisciplinary analyses of gene-brain-behavior relationships.

Bridging cognition, the brain and molecular genetics: evidence from Williams syndrome

Williams syndrome (WMS) is a rare sporadic disorder that yields a distinctive profile of medical, cognitive, neurophysiological, neuroanatomical and genetic characteristics. The cognitive hallmark of WMS is a dissociation between language and face processing (relative strengths) and spatial cognition (profound impairment). Individuals with WMS also tend to be overly social, behavior that is opposite to that seen in autism. A genetic hallmark of WMS is a deletion on chromosome band 7q11.23. Williams syndrome is also associated with specific neuromorphological and neurophysiological profiles: proportional sparing of frontal, limbic and neocerebellar structures is seen using MRI; and abnormal functional organization of the neural systems that underlie both language and face processing is revealed through studies using event-related potentials. The non-uniformity in the cognitive, neuromorphological and neurophysiological domains of WMS make it a compelling model for elucidating the relationships between cognition, the brain and, ultimately, the genes.

Evidence from two genetic syndromes for a dissociation between verbal and visual-spatial short-term memory.

Williams and Down syndromes, two genetic syndromes of abnormal neurodevelopment, are characterized by specific neuropsychological profiles and unique patterns of brain morphology. We find that the superior language ability of subjects with Williams syndrome is accompanied by significantly better performance on a verbal short-term memory task. Conversely, subjects with Down syndrome perform significantly better on a visual-spatial short-term memory task. This double dissociation provides neurogenetic evidence for the distinction between short-term storage for verbal and for visual-spatial stimuli.

''Frog, where are you?'' Narratives in children with specific language impairment, early focal brain injury, and Williams syndrome

In this cross-population study, we use narratives as a context to investigate language development in children from 4 to 12 years of age from three experimental groups: children with early unilateral focal brain damage (FL; N=52); children with specific language impairment (SLI; N=44); children with Williams syndrome (WMS; N=36), and typically developing controls. We compare the developmental trajectories of these groups in the following domains: morphological errors, use of complex syntax, complexity of narrative structure, and types and frequency of evaluative devices. For the children with early unilateral brain damage, there is initial delay. However, by age 10, they are generally within the normal range of performance for all narrative measures. Interestingly, there are few, if any, side specific differences. Children with SLI, who have no frank neurological damage and show no cognitive impairment demonstrate significantly more delay on all morphosyntactic measures than the FL group. Quantitatively, on morphosyntactic measures, the SLI group clusters with those children with WMS who are moderately retarded. Together these data help us to understand the extent and nature of brain plasticity for language development and those aspects of language and discourse that are dissociable.

Is there a social module? language, face processing, and theory of mind in individuals with williams syndrome

Many species can respond to the behavior of their conspecifics. Human children, and perhaps some nonhuman primates, also have the capacity to respond to the mental states of their conspecifics, i.e., they have a theory of mind. On the basis of previous research on the theory-of-mind impairment in people with autism, together with animal models of intentionality, Brothers and Ring (1992) postulated a broad cognitive module whose function is to build representations of other individuals. We evaluate the details of this hypothesis through a series of experiments on language, face processing, and theory of mind carried out with subjects with Williams syndrome, a rare genetic neurodevelopmental disorder resulting in an uneven lin-guisticocognitive profile. The results are discussed in terms of how the comparison of different phenotypes (e.g., Williams syndrome, Down syndrome, autism, and hydrocephaly with associated myelomeningocele) can contribute both to understanding the neuropsychology of social cognition and to current thinking about the purported modularity of the brain.

VI. Genome Structure and Cognitive Map of Williams Syndrome

Williams syndrome (WMS) is a most compelling model of human cognition, of human genome organization, and of evolution. Due to a deletion in chromosome band 7q11.23, subjects have cardiovascular, connective tissue, and neurodevelopmental deficits. Given the striking peaks and valleys in neurocognition including deficits in visual-spatial and global processing, preserved language and face processing, hypersociability, and heightened affect, the goal of this work has been to identify the genes that are responsible, the cause of the deletion, and its origin in primate evolution. To do this, we have generated an integrated physical, genetic, and transcriptional map of the WMS and flanking regions using multicolor metaphase and interphase fluorescence in situ hybridization (FISH) of bacterial artificial chromosomes (BACs) and P1 artificial chromosomes (PACs), BAC end sequencing, PCR gene marker and microsatellite, large-scale sequencing, cDNA library, and database analyses. The results indicate the genomic organization of the WMS region as two nested duplicated regions flanking a largely single-copy region. There are at least two common deletion breakpoints, one in the centromeric and at least two in the telomeric repeated regions. Clones anchoring the unique to the repeated regions are defined along with three new pseudogene families. Primate studies indicate an evolutionary hot spot for chromosomal inversion in the WMS region. A cognitive phenotypic map of WMS is presented, which combines previous data with five further WMS subjects and three atypical WMS subjects with deletions; two larger (deleted for D7S489L) and one smaller, deleted for genes telomeric to FZD9, through LIMK1, but not WSCR1 or telomeric. The results establish regions and consequent gene candidates for WMS features including mental retardation, hypersociability, and facial features. The approach provides the basis for defining pathways linking genetic underpinnings with the neuroanatomical, functional, and behavioral consequences that result in human cognition.

Abnormal Cortical Complexity and Thickness Profiles Mapped in Williams Syndrome

We identified and mapped an anatomically localized failure of cortical maturation in Williams syndrome (WS), a genetic condition associated with deletion of ∼20 contiguous genes on chromosome 7. Detailed three-dimensional (3D) maps of cortical thickness, based on magnetic resonance imaging (MRI) scans of 164 brain hemispheres, identified a delimited zone of right hemisphere perisylvian cortex that was thicker in WS than in matched controls, despite pervasive gray and white matter deficits and reduced total cerebral volumes. 3D cortical surface models were extracted from 82 T1-weighted brain MRI scans (256 × 192 × 124 volumes) of 42 subjects with genetically confirmed WS (mean ± SD, 29.2 ± 9.0 years of age; 19 males, 23 females) and 40 age-matched healthy controls (27.5 ± 7.4 years of age; 16 males, 24 females). A cortical pattern-matching technique used 72 sulcal landmarks traced on each brain as anchors to align cortical thickness maps across subjects, build group average maps, and identify regions with altered cortical thickness in WS. Cortical models were remeshed in frequency space to compute their fractal dimension (surface complexity) for each hemisphere and lobe. Surface complexity was significantly increased in WS (p < 0.0015 and p < 0.0014 for left and right hemispheres, respectively) and correlated with temporoparietal gyrification differences, classified via Steinmetz criteria. In WS, cortical thickness was increased by 5-10% in a circumscribed right hemisphere perisylvian and inferior temporal zone (p < 0.002). Spatially extended cortical regions were identified with increased complexity and thickness; cortical thickness and complexity were also positively correlated in controls (p < 0.03). These findings visualize cortical zones with altered anatomy in WS, which merit additional study with techniques to assess function and connectivity.

IV. Neuroanatomy of Williams Syndrome: A High-Resolution MRI Study

Williams syndrome (WMS), a genetic condition resulting from a contiguous deletion on the long arm of chromosome 7, is associated with a relatively consistent profile of neurocognitive and neurobehavioral features. The distinctiveness and regularity of the profile of learning and behavioral characteristics in this genetic condition suggests that underlying neurobiological correlates may be identifiable. In this initial study, we report findings derived from a high-resolution neuroimaging study of 14 young adult subjects with WMS and an individually matched normal control group. Compared to controls, subjects with WMS were noted to have decreased overall brain and cerebral volumes, relative preservation of cerebellar and superior temporal gyrus (STG) volumes, and disproportionate volume reduction of the brainstem. Analyses also suggested that the pattern of cerebral lobe proportions in WMS may be altered compared to normal controls with a greater ratio of frontal to posterior (parietal+occipital) tissue. Assessment of tissue composition indicated that, relative to controls, individuals with WMS have relative preservation of cerebral gray matter volume and disproportionate reduction in cerebral white matter volume. However, within the cerebral gray matter tissue compartment, the right occipital lobe was noted to have excess volume loss. Combined with our growing knowledge of the function of genes in the commonly deleted region for WMS, more detailed information regarding the structure and function of the WMS brain will provide a unique opportunity for elucidating meaningful correlations amongst genetic, neurobiological, and neurobehavioral factors in humans.

A comparison of sign language and spoken language

Abstract Evidence is presented which suggests that a sign in the American Sign Language takes longer to produce than a spoken word, but that a proposition takes about the same amount of time to produce in either language, or either modality for some signers. Properties of American Sign Language which can account for both of these facts are then discussed.