Pharmacologic modulation of hippocampal activity in psychosis

项目总结/摘要 开发更好的精神分裂症治疗方法需要我们确定新的治疗靶点。一 最近提出的目标是海马活动过度，用神经成像方法证明。新兴 有证据表明，精神分裂症患者海马活动的增加限制了招募神经元的能力。 海马在认知任务的表现。然而，海马神经基础 功能障碍（即，多动和受损的招募）的精神分裂症是知之甚少。为了 为了更好地了解这种潜在治疗靶点的神经机制，我建议a）采取措施 用两种互补的非侵入性神经成像技术检测海马活动，和B）使用 采用双向交叉、随机化、双盲、安慰剂对照设计进行药物干预， 这一假说认为，导致募集受损的多动症是兴奋抑制的结果， 海马体的不平衡这项工作将证明，病理神经过程的基础， 海马活动过度可以通过用一种 药物干预，左乙拉西坦（LEV）。我假设左心室介入治疗 精神分裂症患者的海马活动。首先，动脉自旋标记（ASL）将用于定量 安慰剂和低剂量口服给药后海马前部脑血流量（静息状态活动的指标） 精神分裂症患者和对照组的LEV给药。将测量血清LEV水平以评估 LEV浓度与海马静息态活动变化的关系。这项研究证明了 概念表明，LEV减少前海马静息状态活动，并可以使用ASL量化。 其次，BOLD信号将用于测量安慰剂和口服后的前海马募集， 精神分裂症患者和对照组的低剂量LEV给药。这将揭示一种药理学 干预可以使精神分裂症患者海马募集正常化。第三，关系 评估前海马静息状态活性和募集。这将证明， 静息状态活动可用于预测募集。此外，我们将调查LEV是否 干预可以使精神分裂症患者静息态活动与募集的关系正常化 队列。海马活动的正常化将为精神分裂症的治疗靶点提供新的证据。 这个项目，当与严格的临床和科学培训相结合，将提供一个机会， 与专家进行跨学科合作，掌握神经成像和 干预性研究设计，使我成为神经科学领域的精神病学家和科学家领导者。

PROJECT SUMMARY/ABSTRACT The development of better treatments for schizophrenia requires that we identify novel treatment targets. A recently proposed target is hippocampal hyperactivity, demonstrated with neuroimaging methods. Emerging evidence suggests that increased hippocampal activity in schizophrenia patients limits the ability to recruit the hippocampus during cognitive task performance. However, the neural basis underlying hippocampal dysfunction (i.e., hyperactivity and impaired recruitment) in schizophrenia is poorly understood. In order to better understand the neural mechanisms of this potential treatment target, I propose to a) measure hippocampal activity with two complementary, non-invasive neuroimaging techniques and b) use pharmacologic intervention in a 2-way crossover, randomized, double-blind, placebo-controlled design to test the hypothesis that hyperactivity leading to impaired recruitment is a consequence of an excitation-inhibition imbalance in the hippocampus. This work will demonstrate that the pathologic neural processes underlying hippocampal hyperactivity can be modulated through perturbation of hippocampal micro-circuitry with a pharmacologic intervention, levetiracetam (LEV). I hypothesize that a LEV intervention will normalize hippocampal activity in schizophrenia patients. First, arterial spin labeling (ASL) will be used to quantify anterior hippocampal cerebral blood flow, a measure of resting state activity, after placebo and oral, low-dose LEV administration in schizophrenia patients and controls. Serum levels of LEV will be measured to assess the relationship of LEV concentration with the change in hippocampal resting state activity. This study is a proof of concept to show that LEV reduces anterior hippocampal resting state activity and can be quantified using ASL. Second, the BOLD signal will be used to measure anterior hippocampal recruitment after placebo and oral, low-dose LEV administration in schizophrenia patients and controls. This will reveal whether a pharmacologic intervention can normalize hippocampal recruitment in schizophrenia patients. Third, the relationship between anterior hippocampus resting state activity and recruitment will be assessed. This will demonstrate whether resting state activity can be used to predict recruitment. Additionally, we will investigate whether LEV intervention is able to normalize the relationship of resting state activity and recruitment in the schizophrenia cohort. Normalization of hippocampal activity will provide novel evidence of a treatment target in schizophrenia. This project, when combined with rigorous clinical and scientific training, will provide an opportunity for interdisciplinary collaboration with experts and mastery of multiple techniques in neuroimaging and interventional study design, well-equipping me to become a psychiatrist-scientist leader in neuroscience.