Neural Network Biomarkers for Relational Memory and Psychosis in Schizophrenia

描述（由申请人提供）：精神分裂症（SZ）的神经生物学机制仍然未知，阻碍了有效治疗的发展。病原学相关疾病生物标志物的鉴定及其后续检测作为治疗反应的措施对该领域至关重要。本研究计划旨在测试SZ患者陈述性（即关系性）记忆功能障碍的解剖和功能生物标志物及其与精神病的关系，重点是海马体-新皮层（hip - nc）大脑网络的系统水平改变。我们将在两个层面上进行这项检查：(1)在Hipp电路中，使用高分辨率功能MRI （fMRI）来测试Hipp子场对关系记忆（RM）功能障碍和精神病的贡献；(2)在Hipp- nc网络中，使用标准分辨率fMRI和连接分析（静息状态fMRI， DTI）来测试系统级生物标志物。最终，我们的目标是通过测试Hipp电路和hip - nc网络内部和之间的区域结果之间的相互关系，以及它们与RM行为和精神病表现结果的关联，来定义hip - nc介导的SZ RM功能障碍和精神病的系统级“生物特征”。我们将在30名患有精神分裂情感障碍（SZ）的门诊患者中进行这些实验，并与30名健康个体进行对比。使用尖端的高分辨率和标准分辨率多模态脑成像方法对系统级疾病生物标志物进行测试，使该建议具有高度创新性。本研究结果可能为SZ产生新的hip - nc结合的生物标志物，有助于了解hip - nc系统在认知功能障碍和精神病发病机制中的作用，并有助于未来开发客观的措施来衡量SZ和相关精神疾病的治疗反应。对所提出的研究的追求不仅将促进该研究领域的知识，而且还将为实现候选人培训和职业发展计划的更广泛目标提供有价值的框架。候选人的近期目标是成为深圳转化神经科学研究领域的独立研究者。为了实现这一目标，候选人组织了一个培训计划，包括课程作业、阅读、研讨会、会议，以及与导师和顾问团队的咨询（所有人都积极与导师合作），他们是SZ神经影像学和认知神经科学研究的主要专家，以及系统级分析方法。研究和培训活动将在德克萨斯大学西南医学中心、精神分裂症转化神经科学研究部和高级成像研究中心进行，该中心将为候选人提出的研究和培训计划提供基础设施。该职业发展奖将使候选人的总体目标有助于理解精神病的神经生物学，并为新的治疗开发工作提供信息。

DESCRIPTION (provided by applicant): The neurobiological mechanisms of schizophrenia (SZ) remain unknown, hindering the development of effective treatments. The identification of pathogenetically-relevant disease biomarkers and their subsequent testing as measures for treatment response are critical for the field. This research proposal aims to test anatomical and functional biomarkers for declarative (i.e., relational) memory dysfunction and their associations with psychosis in patients with SZ, with an emphasis on system-level alterations within the hippocampus-neocortical (Hipp-NC) brain network. We will carry out this examination at two levels: (1) within Hipp circuitry, to test Hipp subfield contributions to relational memory (RM) dysfunction and psychosis, using high resolution functional MRI (fMRI), and (2) within the Hipp-NC network, to test system-level biomarkers, using standard resolution fMRI, and connectivity analyses (resting state fMRI, DTI). Ultimately, our goal is to define Hipp-NC-mediated systems-level 'biosignatures' for RM dysfunction and psychosis in SZ by testing inter-relations between the regional outcomes within and across Hipp circuitry and Hipp-NC networks and their association with RM behavioral and psychosis manifestation outcomes. We will conduct these experiments in 30 outpatients with SZ or schizoaffective disorder, contrasted with 30 healthy individuals. It is the testing of system-level disease biomarkers using cutting-edge high- and standard-resolution multimodal brain imaging methodology that make this proposal highly innovative. The outcomes of this research may generate novel Hipp-NC-bound biomarkers for SZ, contribute to understanding the role of Hipp-NC system in pathogenesis of cognitive dysfunction and psychosis, and aid in the future development of objective measures for treatment response in SZ and related psychotic disorders. Pursuit of the proposed studies will not only advance knowledge in this research field, but also provide a valuable framework for achieving the broader aims of the candidate's training and career development program. The candidate's immediate goal is to develop a career as an independent investigator in the field of translational neuroscience research in SZ. To achieve this goal, the candidate has organized a training program involving coursework, readings, workshops, conferences, and consultations with the mentor and the team of consultants (all actively collaborating with the mentor) who are leading experts in neuroimaging and cognitive neuroscience research in SZ, as well as system-level analytic approaches. Research and training activities will be carried out at UT Southwestern Medical Center, the Division of Translational Neuroscience Research in Schizophrenia and the Advanced Imaging Research Center that will provide an infrastructure for the candidate's proposed research and training plan. This career development Award will enable the candidate's overall goals of contributing to the understanding of neurobiology of psychosis and informing new treatment development efforts.