MRS Studies of Glutamate and GABA in Bipolar Dissorder

描述（由申请人提供）：这是k23指导的患者导向研究职业发展奖申请的首次再提交，题为“双相情感障碍中谷氨酸和GABA的MRS研究”。候选人的背景是双相情感障碍（BD）细胞异常的死后研究，他目前是麦克莱恩医院精神分裂症和双相情感障碍项目的主任。目前的建议是允许候选人使用体内神经成像来扩展他对双相障碍细胞异常的发现。磁共振波谱（MRS）是一种非常好的技术，候选人选择在Dr. Perry Renshaw的指导下工作，Perry Renshaw是一位领先的mri专家和McLean脑成像中心主任。考虑到他直接参与了双相障碍患者的临床护理，并与一个领先的MRS研究小组有关系，该候选人很适合开发一个独立的研究项目，将MRS方法应用于双相障碍研究。希望这将有助于更好地了解双相障碍的病理生理和目前的治疗方法，并确定新的治疗靶点。该研究的主要目标是利用最近发展的MRS方法来量化双相障碍患者和健康对照者的脑谷氨酸和γ -氨基丁酸（GABA）水平。谷氨酸和GABA是大脑中最丰富的神经递质，它们的功能需要广泛的神经元-胶质相互作用。因此，它们的水平提供了突触功能和细胞活动的信息。该应用程序的中心假设是，BD的细胞异常将系统地反映在谷氨酸和GABA异常上。将在前扣带皮层和顶枕皮层测量谷氨酸和GABA水平，其中在双相障碍中报告了异常。候选人将利用他的能力，从专门从事双相障碍的临床单位招募患者，以检查疾病阶段（复发与首发）和疾病发作（两个队列中躁狂和抑郁发作的患者，以及接受药物治疗和不接受药物治疗的门诊患者）对测量的影响。统计分析将用于检查这些因素对谷氨酸和GABA水平的影响。作为拟议研究的一部分，候选人寻求以下方面的培训：1)MRS数据分析的技术和方法；2)突触传递与细胞代谢的神经化学；3)伦理临床研究方法。拟议的研究计划、教学课程以及与导师和顾问的合作将促进候选人发展成为一名独立的临床医生和科学家，利用神经影像学研究BD神经化学。双相障碍是一种常见的使人衰弱的疾病。目前的双相障碍治疗是部分有效的，其作用机制尚不清楚。因此，迫切需要针对BD相关生物过程的有效新型治疗方法，而当前的提案旨在满足这一需求。

DESCRIPTION (provided by applicant): This is a first resubmission of a K23-Mentored Patient-Oriented Research Career Development Award application entitled "MRS Studies of Glutamate and GABA in Bipolar Disorder". The candidate's background is in postmortem studies of cellular abnormalities in bipolar disorder (BD), and he is currently the Director of the Schizophrenia and Bipolar Disorder Program at McLean Hospital. The current proposal is designed to allow the candidate to use in vivo neuroimaging to extend his findings of cellular abnormalities in BD. Magnetic resonance spectroscopy (MRS) is an excellent technique for this purpose, and the candidate has chosen to work under the mentorship of Dr. Perry Renshaw, a leading MRSexpert and director of McLean's Brain Imaging Center. Given his direct involvement in the clinical care of patients with BD and relationship with a leading MRS research group, the candidate is well-positioned to develop an independent research program applying MRS approaches to BD studies. It is hoped that this will lead to a better understanding of BD pathophysiology and current treatments, as well as to identification of novel treatment targets. The main goal of the proposed research is to use recently developed MRS approaches to quantify brain glutamate and gamma-aminobutyric-acid (GABA) levels in BD patients and healthy controls. Glutamate and GABA are the most abundant neurotransmitters in the brain, and extensive neuronal-glial interactions are required for their function. Their levels therefore provide information on synaptic function and cellular activity. The central hypothesis of the application is that cellular abnormalities in BD will be systemactically reflected in glutamate and GABA abnormalities. Glutamate and GABA levels will be measured in the anterior cingulate cortex where abnormalities have been reported in BD, and in the parieto-occipital cortex. The candidate will take advantage of his ability to recruit patients from a clinical unit specializing in BD to examine the effects of phase of illness (recurrent vs. first-episode) and disease episode (patients in manic and depressive episodes in both cohorts, as well as medicated and medication-free euthymic outpatients) on the measures. Statistical analyses will be tailored to examine the effects of these factors on glutamate and GABA levels. As part of proposed research, the candidate seeks training in: 1) MRS techniques and methods for MRS data analysis; 2) neurochemistry of synaptic transmission and cellular metabolism; and 3) ethical clinical research methods. The proposed research plan, didactic courses, and work with mentors and advisors will foster the candidate's development into an independent clinician-scientist using neuroimaging to study BD neurochemistry. BD is a common and debilitating illness. Current BD treatments are partially effective, and their mechanisms of action are not well-understood. There is therefore a pressing need for effective novel treatments which target relevant biological processes in BD, and the current proposal aims to contribute to meeting this need.