Imaging Hippocampal Function in Psychosis

摘要(项目摘要) 我们建议通过研究海马区的进化来解析精神障碍的临床异质性。 精神病早期功能障碍(ESOP) 海马体体积变小是慢性精神分裂症最显著的脑部异常之一，但 在精神病的前驱症状和早期阶段不太明显。相比之下，前部的过度活动 在精神病的早期和慢性阶段都观察到了海马体。临床和临床前研究 已经发现兴奋/抑制失衡是海马区过度活动的一个可能的机制 精神错乱。弄清海马区功能障碍的时间和机制将提高我们的干预能力 并防止从早期精神病发展为精神分裂症。 我们建议研究2个员工持股计划队列。ESOP-1将是一个新的急性精神病患者队列，他们将满足 精神分裂症的DSM-5标准A至少1个月，但不超过2年(即，分裂样 精神障碍或早期精神分裂症)。我们预计，在研究结束时，三分之二的ESOP-1队列将具有 进展为精神分裂症，其余三分之一将被诊断为分裂样障碍。员工持股计划- 2是一个具有良好特征的精神分裂症患者样本，他们参与了重复评估 在他们生病的头两年。我们将从ESOP-1中招募30名患者和30名健康对照组 以恢复海马区兴奋/抑制平衡。 我们预测，在ESOP-1队列中，海马体过度活跃，导致关系， 基于海马体的记忆。我们预计只有在以下情况下才能发现前海马区的结构变化 将发展为精神分裂症的ESOP患者。在ESOP-2队列中，我们预测进行性海马区 体积丢失，从前部向后部推进，导致更明显的记忆障碍。 我们预测，恢复正常的兴奋/抑制平衡将改善ESOP的海马区功能 人。 为了检验我们的假设，我们将收集高密度、多维度的精神病评估。我们将使用 海马区的高分辨率分割方案及静息状态和基于任务的功能成像 激活。我们将使用抗癫痫药物左乙拉西坦的单剂量给药来调节 兴奋/抑制平衡。 拟议的纵向成像和药理学成像的结合将使我们能够研究时间和 精神病患者海马区功能障碍的机制。这些方法的整合旨在 建立精神障碍的分期模式，最终目标是帮助早期发现、预防和 治疗。

Abstract (Project Summary) We propose to parse the clinical heterogeneity of psychotic disorders by studying the evolution of hippocampal dysfunction in the early stage of psychosis (ESOP). Smaller hippocampal volume is one of the most significant brain abnormalities in chronic schizophrenia, but is less pronounced in prodromal and early stages of psychosis. In contrast, hyperactivity of the anterior hippocampus has been observed in both early and chronic stages of psychosis. Clinical and preclinical studies have identified excitation/inhibition imbalance as a plausible mechanism for hippocampal hyperactivity in psychosis. Clarifying the timing and mechanism of hippocampal dysfunction will improve our ability to intervene and prevent the progression from early psychosis to schizophrenia. We propose to study 2 ESOP cohorts. ESOP-1 will be a new cohort of acutely ill psychotic patients who meet DSM-5 criteria A for schizophrenia for at least one month, but not more than 2 years (i.e., schizophreniform disorder or early schizophrenia). We expect that, at the end of the study, 2/3 of the ESOP-1 cohort will have progressed to schizophrenia, while the remaining 1/3 will be diagnosed with schizophreniform disorder. ESOP- 2 is a well-characterized sample of schizophrenia patients, who have participated in repeated assessments during the first two years of their illness. From ESOP-1 we will recruit 30 patients and 30 healthy control subjects for the restoration of hippocampal excitation/inhibition balance. We predict that the hippocampus is hyperactive in the ESOP-1 cohort, resulting in perturbations of relational, hippocampal-based memory. We expect to find structural changes of the anterior hippocampus only in those ESOP persons who will progress to schizophrenia. In the ESOP-2 cohort, we predict progressive hippocampal volume loss, advancing from the anterior to the posterior region, resulting in more significant memory deficits. We predict that restoring normal excitation/inhibition balance will improve hippocampal function in ESOP persons. To test our hypotheses, we will collect high-density, multi-dimensional assessments of psychosis. We will use high-resolution parcellation protocols of the hippocampus and functional imaging of resting-state and task-based activation. We will use single dose administration of levetiracetam, an anti-epileptic drug, to modulate excitation/inhibition balance. The proposed combination of longitudinal and pharmacological imaging will allow us to study the timing and mechanism of hippocampal dysfunction in psychotic disorders. The integration of these approaches aims to establish a staging model of psychotic disorders, with the ultimate goal to aid early detection, prevention and treatment.