Imaging White Matter Maturation and Genetic High Risk for Schizophrenia

项目摘要 有一种压倒性的观点认为精神分裂症(SZ)是一种神经发育障碍，由于 有证据表明结构和认知变化出现在不同的疾病阶段。结构工程的时间表 然而，对异常及其与认知病理学的关系却知之甚少。神经认知 障碍，最突出的是语言和工作记忆缺陷，被认为是SZ的核心特征，但 这些缺陷的发展进程各不相同。语言能力似乎在很小的时候就下降了 那些有SZ遗传风险的人，他们此后一直保持稳定的下降，而工作记忆能力 在精神病发作前不久偏离健康的轨迹，并随着疾病的进一步恶化 进步。深圳的语言和工作记忆能力的不同轨迹强烈表明 有不同的潜在病理生理机制。 有证据表明，白质在大脑发育和成熟过程中起着至关重要的作用。 研究已将白质束微结构异常与高危人群认知能力缺陷联系起来。 个人和SZ患者。为了阐明结构-功能的发育时间线 高危人群脑白质与认知能力的关系，我们的目标是描述 与SZ高危个体的神经认知缺陷相对应的白质病理改变。 拟议的项目将分析已经从三个遗传高风险队列收集的数据，这些队列 代表SZ风险的三个关键发展阶段：婴儿期、儿童期和成年期早期。这项研究将 因此，提供与SZ风险和SZ相关的早期和晚期神经发育变化的洞察 能够在特定的发展窗口内确定结构性缺陷的特征。我们计划申请 先进的扩散张量成像方法，以及轨道几何和自由水成像 数据集，允许识别和区分可能存在的局限性白质异常 与体内异常的早期神经发育或较晚成熟的病理有关。 这个项目有两个主要假设：1)我们假设语言缺陷与 稳定的结构差异起源于异常的早期神经发育过程，反映在变化上 在白质语言束中的纤维结构(几何学)；2)我们假设 工作记忆能力与可能受到侮辱时的暂时性或反应性病理有关，并且 这反映在工作记忆下的区域偏离正常的成熟轨迹。 这将是第一项分析遗传高危人群脑白质的研究。 神经发育。这项研究将对我们理解生物学的时间线产生重大影响。 揭示与SZ风险相关的功能相关的机制，同时发现与 功能脆弱性和确定治疗干预措施何时最有效的窗口。

Project Summary There is an overwhelming belief that schizophrenia (SZ) is a neurodevelopmental disorder, due to evidence that structural and cognitive changes emerge at different illness stages. The timeline of structural abnormalities and their relationship to cognitive pathologies, however, is poorly understood. Neurocognitive impairments, most prominently language and working memory deficits, are considered core features of SZ, but the developmental progression of these deficits varies. Language abilities appear to be reduced very early in those at genetic risk for SZ, and they remain stably reduced thereafter, whereas working memory abilities diverge from a healthy trajectory shortly before the onset of psychosis and further deteriorate with illness progression. The differential trajectories of language and working memory capabilities in SZ strongly suggest there are distinct underlying pathophysiological mechanisms. Evidence suggests that white matter plays a crucial role in brain development and maturation, and studies have linked microstructural abnormalities in white matter tracts to deficits in cognitive abilities in at-risk individuals and SZ patients. In order to elucidate the developmental timeline of the structure-function relationship between white matter and cognitive abilities in at risk individuals, we aim to characterize pathological alterations in white matter that correspond to neurocognitive deficits in SZ risk individuals. The proposed project will analyze already collected data from three genetic high risk cohorts that represent three key developmental stages of SZ risk: infancy, childhood, and early adulthood. This study will therefore provide insight into both early and late neurodevelopmental changes associated with SZ risk and enable the characterization of structural deficits within specific developmental windows. We plan to apply advanced diffusion tensor imaging methodologies along with tract geometry and free water imaging to the datasets, allowing for the identification and differentiation of localized white matter abnormalities that may be related to aberrant early neurodevelopmental or later maturational pathologies in vivo. This project has two primary hypotheses: 1) We hypothesize that deficits in language are related to stable structural differences originating in aberrant early neurodevelopmental processes, reflected by changes in fiber architecture (geometry) in white matter language tracts; 2) We hypothesize that the deterioration of working memory abilities is related to a transient or reactive pathology to the presence of a possible insult, and this is reflected by deviations from normal maturational trajectories in tracts underlying working memory.. This will be the first study to analyze white matter from genetically at-risk individuals across the range of neurodevelopment. This study will significantly impact our understanding of the timeline of biological mechanisms that underlie functional correlates associated with SZ risk while uncovering biomarkers linked to functional vulnerabilities and identifying windows when therapeutic interventions would be most effective.