Neural correlates of working memory in children with 22q11.2 deletion syndrome

描述（申请人提供）：染色体22q11.2缺失综合征是人类最常见的染色体微缺失综合征，可导致多种医学问题和神经认知缺陷。这些神经认知缺陷对这些儿童在学业任务和日常生活中取得成功至关重要的功能产生不利影响。此外，这些儿童作为青少年和成年人面临着精神分裂症和其他使人衰弱的精神疾病的极高风险。在这些精神疾病的过程中，预先存在的认知缺陷变得更糟，并增加了他们面临的障碍。因此，迫切需要采取干预措施，以减轻这些人的神经认知缺陷的负担，并增加他们的功能。设计干预措施的关键第一步是了解认知缺陷的机制，在本提案中，PI Shashi博士将获得必要的技能，以了解22q11DS儿童与工作记忆相关的神经元功能和结构。具体目标1：确定22q11DS儿童工作记忆激活的神经元区域。这一目标是基于假设1，即与对照组相比，22q11DS儿童的背外侧前额叶皮层（DLPFC）、扣带和顶叶区域的激活模式在工作记忆任务中会减少。具体目标2：检查22 q11 DS儿童工作记忆激活区域中白色物质的结构连接模式。这是基于假设2，即与对照受试者相比，患有22 q11 DS的儿童的DLPFC、扣带回和顶叶区域的神经元完整性和连接性将降低。为了实现这些目标，沙希博士将在本奖励期的前6个月接受功能磁共振成像和扩散张量成像领域的培训，这将使她能够检查使用工作记忆时激活的大脑区域以及这些区域之间的白色物质连接。该培训将在杜克大学的艾伦宋博士和哈佛医学院的Matcheri Keshavan博士的指导下进行。该项目将提供有关22q11DS儿童工作记忆基础的信息，并提供一个框架，以便将来评估干预措施的有效性。 公共卫生相关性：了解22q11DS儿童工作记忆的神经元相关性将有助于提供一种评估干预措施改善工作记忆后改善的方法。

DESCRIPTION (provided by applicant): Chromosome 22q11.2 deletion syndrome is the most common chromosome microdeletion syndrome in human beings and results in multiple medical problems and neurocognitive deficits. These neurocognitive deficits adversely affect functions that are critical to these children's success in academic tasks and in daily life. Additionally, these children face an extraordinarily high risk of schizophrenia and other debilitating mental illnesses as adolescents and adults. During the course of these mental illnesses, the pre-existing cognitive deficits become worse and add to the handicaps that they face. Thus, there is an urgent need for interventions to reduce the burden of the neurocognitive deficits upon these individuals and to increase their functionality. A critical first step to designing an intervention is to understand the mechanisms of the cognitive deficits and in this proposal the PI, Dr. Shashi will acquire the necessary skills to understand the neuronal function and structure related to working memory in children with 22q11DS. The aims are as follows: Specific Aim 1: Ascertain neuronal areas activated by the use of working memory in children with 22q11DS. This aim is based on hypothesis 1 which is that children with 22q11DS will have decreased activation patterns in the dorsolateral prefrontal cortex (DLPFC), cingulate and parietal areas of the brain with a working memory task, compared to control subjects. Specific Aim 2: Examine the patterns of structural connectivity of white matter in the areas activated by working memory in children with 22q11DS. This is based on hypothesis 2 which is that children with 22q11DS will have reduced neuronal integrity in and reduced connectivity between the DLPFC, cingulate and parietal areas, compared to control subjects. In order to achieve these aims, Dr.Shashi will spend the first 6 months of this award period to acquire training in the fields of functional magnetic resonance imaging and diffusion tensor imaging, which would allow her to examine the areas of the brain that are activated when working memory is used and the white matter connections between these areas. This training will occur under the mentorship of Drs. Allen Song of Duke University and Matcheri Keshavan of Harvard Medical School. This project will provide information about the basis of working memory in children with 22q11DS and a framework upon which the efficacy of interventions can be assessed in the future. PUBLIC HEALTH RELEVANCE: Understanding neuronal correlates of working memory in children with 22q11DS will help to provide a way to assess improvements after interventions to improve working memory.