Pharmacologic modulation of hippocampal activity in psychosis

项目摘要/摘要 精神分裂症更好的治疗方法的发展要求我们确定新的治疗目标。一个 最近提出的靶点是海马区的过度活动，用神经成像方法证实。新兴 有证据表明，精神分裂症患者海马区活动增加限制了招募 海马体在认知任务中的表现。然而，海马区的神经基础 精神分裂症的功能障碍(即多动症和招募障碍)目前还知之甚少。为了 为了更好地了解这一潜在治疗靶点的神经机制，我建议采取一种措施 两种互补的非侵入性神经成像技术和b)用途 药物干预在双向交叉、随机、双盲、安慰剂对照设计中的应用 认为过度活动导致招募受损是兴奋抑制的结果的假说 海马体失衡。这项工作将证明潜在的病理神经过程 海马多动可以通过扰动海马微电路来调节。 药物干预，左乙拉西坦(Lev)。我假设利福平的干预会使 精神分裂症患者的海马区活动。首先，将使用动脉自旋标记(ASL)来定量 服用安慰剂和口服低剂量药物后，衡量静息状态活动的指标--海马区前脑血流量 精神分裂症患者和正常对照的利培酮应用。将测定血清LEV水平以评估 LEV浓度与海马静息状态活动变化的关系。这项研究证明了 概念表明，LEV减少了海马区前静息状态的活动，并可以用ASL进行量化。 第二，大胆的信号将被用来测量服用安慰剂和口服后的海马区前部招募， 精神分裂症患者和对照组的小剂量利维他汀治疗。这将揭示一种药理学 干预可以使精神分裂症患者的海马区募集正常化。第三，两国关系 将评估前海马区静息状态下的活动和招募情况。这将证明是否 静息状态的活动可以用来预测招募情况。此外，我们将调查Lev是否 干预能够使精神分裂症患者静息状态活动与招募的关系正常化 一群人。海马区活动的正常化将为精神分裂症的治疗靶点提供新的证据。 该项目与严格的临床和科学培训相结合，将为 与专家进行跨学科合作，并掌握神经成像和 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袖。

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.