The Impact of the Williams Syndrome Mutations on Neural
James S. McDonnell Foundation Collaborative Activity Award:
WHY THE NEED FOR A COLLABORATIVE PROJECT?
The ambitious goals of this proposal are far beyond what could be accomplished by individuals working independently. Clearly, without the impetus of this proposal, many if not all of the proposed experiments could not, and would not, be carried out by the individual collaborators. For example, while Dr. Bellugi has carried out extensive studies on the cognitive neuroscience of Williams syndrome, she has neither the expertise nor facilities to attempt the production of animal models of the disorder; thus the collaboration with Drs. Amaral and Suomi. Similarly, while Dr. Amaral is involved in primate studies of social behavior, without this program, he would not be pursuing either the molecular lesioning techniques developed by Dr. Callaway nor the Williams gene expression analysis that is proposed with Dr. Korenberg. Moreover, this group uniquely facilitates the translation to animal and cellular models of Dr. Korenberg’s work identifying genes for cognitive systems in humans as proposed with Drs. Amaral, Callaway and Suomi. And Dr. Raichle would not be directing his substantial expertise in neuroimaging to collaborative studies of the neural basis of social cognition in Williams without Drs. Bellugi and Korenberg. More to the point, however, the genes related to Williams systems will be used as probes to attempt to identify brain systems in the macaque monkey that may be intimately associated with the mediation of social behavior. Similarly, metabolic and fMRI techniques will attempt to define brain regions in Williams subjects that are associated with hypersociability. And finally, Dr. Bellugi's experimental studies of social cognition in Williams syndrome subjects with full or smaller deletions integrated with Dr. Korenberg’s molecular genetic analysis of the same subjects’ deletions will be central to our understanding of the unique contribution of specific genes to social behavior. Thus, the genetic basis of sociability in Williams syndrome, and the deletions of individuals different size deletions, will provide critical directions for understanding the social brain. In order to open the window of opportunity provided by Williams syndrome, we will need the combined expertise of the listed collaborators all focused on the projects that are outlined below. Some of these projects require the development of new tools, some require pilot studies before full-fledged projects can be started and the technical difficulty of some make them risky. These are, however, highly integrated projects, and taken together, we believe this program is highly consistent with the aims and spirit of the 21st Century Science Initiative “Bridging Brain, Mind and Behavior”; we respectfully submit it for consideration of funding by the James. S. McDonnell Foundation. A sampling of the research that we propose to conduct includes the following:
Project 1: A comprehensive analysis of social cognition in Williams syndrome individuals with different size deletions (Bellugi and Korenberg).
In order to fully capitalize on this unique resource, the hypersociability described in Williams syndrome must be neuropsychologically characterized at multiple levels. For example, we plan experiments investigating face processing and the neural underpinnings of social judgement. We will employ some tasks, such as dyadic social encounters, that will also be carried out with the nonhuman primate. These tasks will be used with Williams individuals having the full deletion as well as with the non hypersocial Williams individuals who may have smaller deletions. One anticipated outcome is that we will identify subsets of genes that will be consistently associated with alterations in the social behavior domain. Some of the assessments that are anticipated include:
1) Evaluation of dyadic social interactions of Williams individuals with familiar versus unfamiliar adults, building on informative studies of inhibited children (Kagan et al, 1998) and paralleling studies by Amaral with monkeys (Emery et al, 2001).
2) Studies of the capacity for identification of faces and facial expressions. We will also use the preferential looking paradigm for faces versus objects; similar studies will be employed by Amaral with monkeys who have undergone manipulations of the amygdala.
3) Studies of ‘approachability’ and other aspects of social cognition used with bilateral amygdala damaged patients (Adolphs, et al, 1998; 1999; Bellugi, et al, 1999)
4) Studies probing the perception and expression of empathy and social understanding (Bellugi, et al, 2001, Tager-Flusberg, et al, in press)
5) Map a specific temperamental profile of Williams with, for example, the Temperament and Character Inventory, which has already been adapted for use with nonhuman primates (Cloninger, et al, 1994).
6) Characterize positive and negative emotional and social responses on a Temperament Behavior Scale adapted from Goldsmith & Rothbart, 1992; see Jones, et al, 2000.
We have found abnormalities in the amygdala in Williams that may be one factor underlying their sociability (Galaburda & Bellugi, 2000). Moreover, we have investigated social behavior experimentally in a paradigm that allows us to compare their social judgements of unfamiliar faces to those of patients with bilateral amygdala damage (Bellugi, Adolphs et al, 1999, Figure above). The Social Cognitive Battery outlined here will further provide specific quantitative assessments for the investigation of the unusual personality of Williams syndrome involving hypersociability. By studying individuals with different size deletions, we expect to find clues to the function of individual genes and their combinations. For example, there is a strong link between the specific heart defect found in Williams and the absence of one copy of the elastin gene. We now propose to link other genes or regions deleted in Williams with specific personality characteristics of the syndrome and to the neural systems and pathways underlying them.
The major specific aim of this project is to fully characterize the areas of altered social cognition in Williams syndrome subjects who have different variants of the Williams gene deletion. The elucidation of a consistent profile of social cognition in Williams with a typical deletion lays the foundation for all other aspects of this proposal, including brain imaging, comparisons with individuals with smaller deletions, monkeys with amygdala damage and/or molecular/genetic manipulations.
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