Visuospatial Cognitive Deficit in Del22q11.2 Syndrome

描述(由申请人提供)：拟议研究计划的中心目标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。拟议的系列研究直接建立在第一个供资阶段(4/1/03-3/31/08)测试的探索性分析的基础上。具体地说，我们认为这种遗传综合征导致了用于基本时空认知的清晰描绘的神经回路的结构和功能的早期发育变化。在儿童时期，由于空间和时间表征在构建过程中所起的中心作用，这种功能障碍会在基本的幅度和数字过程中级联成损害。我们认为这是由于“时空超粒度”，即颗粒尺寸的增大，从而降低了时空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加工中引入错误，这种表征退化定义了假设的“这些基本过程中的变化将产生对视觉空间和数字认知领域的[...]损害的解释”(前一申请)。其结果是，时空过程的发展是非典型的，因此在非语言认知领域产生了典型的损伤，这是22q的一个显著特征。染色体22q11.2缺失综合征(包括DiGeorge综合征、Shprint-zen综合征和血管心面综合征)相当普遍(约1：4000活产)，但对其神经认知影响知之甚少。研究设计了两个特定的目标：1)识别时空加工交互作用中的功能障碍，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础。前者将使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验特定的神经回路假说。通过将22Q儿童的结果与典型发育对照组和性染色体非整倍体儿童的结果进行比较，将解决特异性问题。性染色体非整倍体是另一个空间能力强于语言能力的发育障碍群体。我们期望研究结果能为22q的时空和数字损伤提供神经认知解释，并在下一个资助阶段直接转化为治疗干预措施。公共卫生相关性： 这个项目测试了患有一种常见但尚不为人所知的遗传性疾病--染色体22q11.2缺失--的儿童大脑和思维的变化。这一描述可能解释了他们所经历的学习困难。如果这一解释得到这项研究的支持，那么通过利用研究结果设计基于计算机的干预措施，可以减少或补救在思考和推理空间、时间和数字测量方面的问题，从而使数万名儿童受益。

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.