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孩子在学业和日常生活中取得成功至关重要的功能产生了不利影响。此外，这些儿童在青少年和成年后面临着精神分裂症和其他令人衰弱的精神疾病的极高风险。在这些精神疾病的过程中，先前存在的认知缺陷变得更糟，并增加了他们面临的障碍。因此，迫切需要干预措施来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，在这项建议中，沙希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，即与对照组受试者相比，患有22q11DS的儿童在工作记忆任务中，大脑背外侧前额叶皮质(DLPFC)、扣带回和顶叶区域的激活模式将减少。具体目标2：研究22q11DS儿童工作记忆激活的脑白质结构连接模式。这是基于假设2，即与对照组相比，患有22q11DS的儿童DLPFC、扣带回和顶叶之间的神经元完整性和连接性降低。为了实现这些目标，Shashi博士将在获奖期的前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脑白质连接。这次培训将在杜克大学的Allen Song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，以便在未来评估干预措施的效果。 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方法来评估干预后改善工作记忆的情况。

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.