Establishing a Task-evoked Magnetic Resonance Spectroscopy Approach for Testing the GABA Deficit Hypothesis in Schizophrenia

项目摘要/摘要 在美国和全世界，精神分裂症是所有疾病中最沉重的公共卫生负担之一。 在它的各种症状中，人们现在已经很好地认识到认知缺陷是导致这种情况的重要因素 负担。然而，目前可用的治疗方法充其量只能为这些症状提供适度的好处。这个 识别认知障碍的神经机制将有助于开发新的治疗方法 以及通过确定治疗目标的预防策略。GABA缺乏假说代表了 对精神分裂症认知缺陷的神经基础的最令人信服的解释。它提出， 背外侧前额叶皮质(DLPFC)GABA合成减少导致局部环路损伤 精神分裂症患者的功能和认知。推进这一假说的主要障碍之一 一直无法获得明确的证据证明活体人存在GABA缺陷 精神分裂症。这一证据不仅为GABA缺乏症假说提供了关键的验证，而且 也将为建立具有研究和临床实用的生物标记物铺平道路。奠基 GABA缺乏症假说一直以来都证明了合成能力的降低。 精神分裂症患者死后大脑中的GABA。这一始终如一的有力证明 预测精神分裂症患者DLPFC中GABA浓度降低，这应该是可以检测到的 活体磁共振波谱(MRS)。然而，事实证明，很难表现出始终如一或稳健的一面 精神分裂症患者使用MRS的缺陷这引起了人们的关注，即目前可用的活体MRS方法用于 测量GABA有太多的局限性，无法充分检验GABA缺陷假说。致信地址 鉴于此，我们建议建立一种新的体内测定GABA的方法。这种新方法需要 与目前的方法相比，这是一种根本不同的方法。虽然标准方法测量 基线的神经化学水平(REST)，我们将测量任务诱发的GABA水平与 基线。这种新方法的创新旨在修复一些最重要的 与GABA的MRS测量相关的限制，并优化我们检测到真实GABA的机会 精神分裂症的缺陷。

PROJECT SUMMARY / ABSTRACT Schizophrenia carries one of the heaviest public health burdens of any illness in the U.S. and worldwide. Among its diverse symptoms, it is now well recognized that cognitive deficits are important contributors to this burden. However, currently available treatments provide, at best, modest benefits for these symptoms. The identification of the neural mechanisms of cognitive deficits will facilitate the development of new treatments and preventative strategies by identifying treatment targets. The GABA deficit hypothesis represents one of the most compelling explanations of the neural basis of cognitive deficits in schizophrenia. It proposes that decreased GABA synthesis in the dorsolateral prefrontal cortex (DLPFC) leads to impairments in local circuit function and cognition in schizophrenia. One of the major impediments to the advancement of this hypothesis has been the inability to obtain clear evidence for the presence of GABA deficits in living individuals with schizophrenia. This evidence would not only provide critical validation of the GABA deficit hypothesis, but would also pave the way for the establishment of biomarkers with research and clinical utility. The foundation of the GABA deficit hypothesis has been the consistent demonstration of reduction in the synthesis capacity for GABA in the post-mortem brains of individuals with schizophrenia. This consistent demonstration strongly predicts reduced concentration of GABA in the DLPFC in schizophrenia, which should be detectable using in vivo magnetic resonance spectroscopy (MRS). However, it has proven difficult to show consistent or robust deficits in schizophrenia using MRS. This has raised concerns that currently available in vivo MRS methods for measuring GABA suffer from too many limitations to adequately test the GABA deficit hypothesis. To address these concerns, we propose establishing a new in vivo method for measuring GABA. This new method takes on a fundamentally different approach compared to current methods. While standard methods measure neurochemical levels at baseline (rest), we will measure task-evoked changes in GABA level compared to baseline. The innovations of this new method have been designed to remediate some of the most important limitations associated with MRS measurements of GABA and to optimize our chances of detecting true GABA deficits in schizophrenia.