The central aim of the proposed research program is to evaluate a set of specific hypotheses about the basis for nonverbal cognitive impairments in children with chromosome 22q11.2 deletion syndrome (22q). The proposed series of studies builds directly upon the exploratory analyses tested in the first period of funding (4/1/03 - 3/31/08). Specifically, we propose that this genetic syndrome leads to early developmental changes in the structure and function of clearly delineated neural circuits for basic spatiotemporal cognition. During childhood, this dysfunction cascades into impairments in basic magnitude and then numerical processes, because of the central role that representations of space and time play in their construction. We propose that this is due to "spatiotemporal hypergranularity";the increase in grain size and thus reduced resolution of mental representations of spatial and temporal information. By raising detection thresholds and introducing error into all spatiotemporal processing, this representational degradation defines the hypothesized "alterations in these basic processes [that] will generate explanations of [...] impairments in the domains of visuospatial and numerical cognition" (p.1 previous application). The result is that spatiotemporal processes develop atypically and thereby produce the characteristic impairments in nonverbal cognitive domains that are a hallmark feature of 22q. The chromosome 22q11.2 deletion syndrome (encompassing DiGeorge, Shprintzen and Velocardiofacial Syndromes) is quite prevalent (~1:4000 live births) yet little is known about its neurocognitive implications.
Two Specific Aims are designed to 1) Identify dysfunctions in the interaction of spatial and temporal processing and measure the resolution of spatiotemporal attentional selection, and 2) Identify neural substrates of spatiotemporal dysfunction and of hypergranularity. The former will employ a battery of cognitive and psychophysical experiments to define and measure spatiotemporal cognitive impairments in children with 22q. The latter will examine a specific neural circuitry hypothesis using structural, connectivity and functional measures. Specificity will be addressed by comparing results from children with 22q to typically developing controls and those with sex chromosome aneuploidies, another developmental disability group with stronger spatial than verbal abilities. We expect results to create a neurocognitive explanation of spatiotemporal and numerical impairments in 22q specific enough to be directly translated into therapeutic interventions in the next funding period.
This project tests a very specific account of changes in the minds and brains of children with a common but ill-understood genetic disorder called chromosome 22q11.2 deletion. This account might explain the learning difficulties that they experience. If this explanation is supported by the research, problems in thinking and reasoning about measurements of space, time and numbers could be reduced or remedied by using the results to design computer based interventions that could benefits many tens of thousands of children.
|Schneider, Maude; Debbané, Martin; Bassett, Anne S et al. (2014) Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry 171:627-39|
|Sellier, Chantal; Hwang, Vicki J; Dandekar, Ravi et al. (2014) Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome. PLoS One 9:e103884|
|Wong, Ling M; Riggins, Tracy; Harvey, Danielle et al. (2014) Children with chromosome 22q11.2 deletion syndrome exhibit impaired spatial working memory. Am J Intellect Dev Disabil 119:115-32|
|Hwang, Vicki J; Maar, Dianna; Regan, John et al. (2014) Mapping the deletion endpoints in individuals with 22q11.2 deletion syndrome by droplet digital PCR. BMC Med Genet 15:106|
|Villalon-Reina, Julio; Jahanshad, Neda; Beaton, Elliott et al. (2013) White matter microstructural abnormalities in girls with chromosome 22q11.2 deletion syndrome, Fragile X or Turner syndrome as evidenced by diffusion tensor imaging. Neuroimage 81:441-54|
|Srivastava, Siddharth; Buonocore, Michael H; Simon, Tony J (2012) Atypical developmental trajectory of functionally significant cortical areas in children with chromosome 22q11.2 deletion syndrome. Hum Brain Mapp 33:213-23|
|Simon, Tony J (2011) Clues to the foundations of numerical cognitive impairments: evidence from genetic disorders. Dev Neuropsychol 36:788-805|
|Awate, Suyash P; Yushkevich, Paul A; Song, Zhuang et al. (2010) Cerebral cortical folding analysis with multivariate modeling and testing: Studies on gender differences and neonatal development. Neuroimage 53:450-9|
|Stoddard, Joel; Niendam, Tara; Hendren, Robert et al. (2010) Attenuated positive symptoms of psychosis in adolescents with chromosome 22q11.2 deletion syndrome. Schizophr Res 118:118-21|
|Karayiorgou, Maria; Simon, Tony J; Gogos, Joseph A (2010) 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nat Rev Neurosci 11:402-16|
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