Brain Function and Structure in Young Children at Familial Risk for Schizophrenia

描述（由申请人提供）：精神病预测标志物的识别是精神分裂症早期干预和预防策略发展的核心。没有尝试针对精神病前期和前驱期的一级或二级预防策略，因为在轻度精神病症状出现之前的青春期之前（即在假定的“前驱期”之前）缺乏生物标志物或扎实的病理生理学知识。因为有一致的证据表明，那些后来患上精神分裂症的人在童年早期就开始出现显著的神经心理和社会缺陷，所以有充分的理由相信，大脑异常在青少年前就存在，但目前还没有证据表明这一时期存在这种异常。目前的建议旨在开始填补这一关键的知识空白。事实上，精神分裂症的一些早期症状，如自我意识障碍，以及反映元认知受损的症状，如自我-他人界限受损，在我们打算研究的年龄范围内，经常出现在精神分裂症（ARS）风险人群中。我们假设“早期发病前”时期的神经生物学特征是大脑发育不成熟，反映在皮层厚度改变、海马和内侧前额皮质体积减少、信息处理异常和连接功能障碍上。这项初步研究的重点是8- 11岁有精神分裂症风险的儿童，旨在通过横断面设计测试有关脑功能、结构和认知的假设，为后续拨款研究青春期前ARS儿童脑结构和功能的纵向进化奠定基础。这个项目将集中在一个新颖的，但非常有前途的新研究领域；通过（使用功能性核磁共振成像）评估处于危险中的儿童内在体验的神经基质：1)大脑功能的“默认模式”；2)“自我反思”（对自己或他人的反思）背后的神经网络。此外，我们将把我们之前在青少年中的工作扩展到儿童；3)工作记忆过程中大脑功能的改变；4)结构异常。关于在幼儿中进行这些成像研究的可行性，研究目标与强调新颖性和创新性的R21指南一致。此外，这项研究与2008年NIMH战略计划是一致的，在该计划中，预测和预防精神分裂症和有患病风险的人的残疾是NIH的关键优先事项。

DESCRIPTION (provided by applicant): The identification of markers for the prediction of psychosis is central to the development of early intervention and prevention strategies for schizophrenia. Primary or secondary prevention strategies oriented to the pre-psychosis and pre-prodromal periods have not been attempted because of an absence of biomarkers or solid knowledge of pathophysiology in the period before adolescence prior to the emergence of mild psychotic symptoms (i.e., prior to the putative "prodrome"). Because there is consistent evidence of significant neuropsychological and social deficits beginning in early childhood of people who later develop schizophrenia, there is strong reason to believe that brain abnormalities are present in the preteen years, but there is no evidence as yet about such abnormalities in that period. The present proposal aims to begin to fill that critical gap of knowledge. Indeed, some of the earliest symptoms of schizophrenia such as disturbances in the sense of self, and those that reflect impaired metacognition such as impaired self-other boundaries are frequently present in those at risk for schizophrenia (ARS) in the age range we intend to study. We hypothesize that the neurobiology of the "early premorbid" period, is characterized by brain dysmaturation, reflected in altered cortical thickness, volume reduction in hippocampus and medial prefrontal cortex, abnormal information processing and dysfunctional connectivity. This preliminary study, focused on children at risk for schizophrenia, ages 8- 11, is designed to test hypotheses about brain function, structure, and cognition in a cross-sectional design that will lay a foundation for subsequent grants designed to study the longitudinal evolution of brain structure and function in prepubertal ARS children. This project will focus on a novel, but highly promising area of new research; the neural substrates of the inner experience of the child at risk, by evaluating (using functional MRI): 1). the "default mode" of brain function and; 2). the neural network underlying 'self reflection' (reflection about oneself or others). Moreover, we will extend to childhood our previous work in adolescents demonstrating; 3). altered brain function during working memory and 4). structural abnormalities. The study goals are consistent with the R21 guidelines emphasizing novelty and innovation, in regard to the feasibility of conducting these imaging studies in young children. Moreover, the study is consistent with the 2008 NIMH Strategic Plan in which prediction and prevention of schizophrenia and disability in those at risk for the illness are key NIH priorities.