Visuospatial Cognitive Deficit in Del22q11.2 Syndrome

描述（由申请人提供）：拟议研究项目的中心目的是评估一组关于染色体22q11.2缺失综合征（22q）儿童非语言认知障碍基础的具体假设。拟议的一系列研究直接建立在第一期资助（2003年4月1日至2008年3月31日）所测试的探索性分析的基础上。具体来说，我们认为这种遗传综合征导致了基本时空认知神经回路结构和功能的早期发育变化。在儿童时期，由于空间和时间的表征在它们的构建中起着核心作用，这种功能障碍级联到基本大小和数字过程的损伤。我们认为这是由于“时空超粒度”；晶粒尺寸的增加，从而降低了空间和时间信息的心理表征的分辨率。通过提高检测阈值并在所有时空处理中引入错误，这种表征性退化定义了假设的“这些基本过程中的变化，将产生对……的解释”。在视觉空间和数字认知领域的损伤”（p.1先前的应用）。结果是非典型的时空过程发展，从而产生非语言认知领域的特征性损伤，这是22q的一个标志性特征。染色体22q11.2缺失综合征（包括DiGeorge、Shprintzen和心面疾速综合征）相当普遍（约1:4000活产），但对其神经认知意义知之甚少。两个特定目标旨在1)识别时空加工交互中的功能障碍，并测量时空注意选择的分辨率；2)识别时空功能障碍和超粒度的神经基质。前者将采用一系列认知和心理物理实验来定义和测量22q儿童的时空认知障碍。后者将使用结构，连通性和功能测量来检查特定的神经回路假设。特异性将通过比较22q儿童与典型发育对照组和性染色体非整倍体儿童（另一种发育障碍群体，空间能力强于语言能力）的结果来解决。我们期望研究结果能够为22q的时空和数值损伤提供一种神经认知解释，足以在下一个资助期直接转化为治疗干预。公共卫生相关性：

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.