Imaging Hippocampal Function in Psychosis

摘要（Project Summary） 我们建议通过研究海马神经元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）。 海马体积变小是慢性精神分裂症最显著的脑异常之一， 在精神病的前驱期和早期阶段不太明显。相反，前额叶的过度活跃 在精神病的早期和慢性阶段都观察到海马体。临床和临床前研究 已经确定兴奋/抑制失衡是海马活动过度的合理机制， 精神病阐明海马功能障碍的发生时间和机制将提高我们的干预能力 防止早期精神病发展为精神分裂症 我们建议研究2个ESOP队列。ESOP-1将是一个新的急性精神病患者队列， 精神分裂症的DSM-5标准A至少一个月，但不超过2年（即，分裂样 精神分裂症或早期精神分裂症）。我们预计，在研究结束时，2/3的ESOP-1队列将有 进展为精神分裂症，而其余1/3将被诊断为精神分裂症样障碍。员工持股计划- 2是精神分裂症患者的良好特征样本，他们参加了重复评估 在他们患病的头两年。从ESOP-1中，我们将招募30名患者和30名健康对照受试者 恢复海马兴奋/抑制平衡。 我们预测ESOP-1队列中海马过度活跃，导致关系， 基于校园的记忆。我们希望只在那些 员工持股计划的人会发展成精神分裂症。在ESOP-2队列中，我们预测进行性海马 体积损失，从前部向后部区域推进，导致更显著的记忆缺陷。 我们预测ESOP中恢复正常的兴奋/抑制平衡将改善海马功能 人士 为了验证我们的假设，我们将收集高密度，多维度的精神病评估。我们将使用 海马的高分辨率分组协议和静息状态和基于任务的功能成像 activation.我们将使用抗癫痫药物左乙拉西坦单剂量给药，以调节 兴奋/抑制平衡 纵向和药理学成像的拟议组合将使我们能够研究的时间和 精神障碍中海马功能障碍的机制整合这些方法的目的是 建立一个精神障碍的分期模型，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.