Neuroimaging mechanisms of overlap between alcoholism and bipolar disorder

简介（由申请人提供）：Prisciandaro博士是南卡罗来纳医科大学（MUSC）精神病学临床神经科学部门（CND）的博士后；他将在2012年7月完成他的奖学金后加入该学院，担任助理教授。Prisciandaro博士通过美国国立卫生研究院（NIH/NIAAA）寻求指导的面向患者的研究职业发展奖（K23），以促进他作为一名独立调查员的职业生涯，在同时发生的酒精使用和双相情感障碍的个体中进行面向患者的研究。候选人：Prisciandaro博士是一名临床心理学家，在物质使用和情绪障碍的研究和实践、定量方法和功能磁共振成像（fMRI）方面接受过广泛的培训。他的长期职业目标是成为以患者为导向的物质使用和情绪障碍研究领域的独立临床科学家，重点是使用神经影像学来开发和测试共同发生的酒精使用和双相情感障碍的机制模型。为了实现这一目标，普里西安达罗博士需要额外的培训。在拟议的奖项期间，Prisciandaro博士将1)获得酒精使用和双相情感障碍的神经生物学的复杂知识，2)学习如何设计，实施和分析fMRI和质子磁共振波谱（1H-MRS）实验，以调查酒精使用和双相情感障碍的神经生物学，3)增强现有的临床研究技能，以及4)改善资助，以便成功竞争独立研究奖（R01）。环境：MUSC在成瘾教育方面排名全国前10位，MUSC医学院有7个系在NIH资助方面排名全国前25位，其中包括精神病学系。成瘾合作跨越多个部门，包括4个NIH中心和2个T32成瘾研究培训资助。各院系有30多名教师从事成瘾研究；其中一些教员将担任导师。Prisciandaro博士建议的导师/合作者是国际和国内的专家，包括dr。雷蒙德·安东、简·约瑟夫、杜鲁门·布朗、凯瑟琳·布雷迪、玛丽·菲利普斯（非现场）、艾伦·斯万（非现场）、彼得·卡利瓦斯、休·迈里克和布莱恩·托利弗。研究程序将通过临床神经科学部门（CND）进行。布雷迪主任博士将为执行拟议的研究提供基础设施。神经成像将在MUSC的高级成像研究中心进行（CAIR； brown博士-主任）。CAIR的西门子3T Trio MRI具有集成的功能磁共振成像范例设备，具有100%的研究任务，并伴有全面的信息学支持。通过MUSC的药物和酒精项目中心、神经科学系、南卡罗来纳临床和转化研究所以及生物统计和流行病学司，可以进一步提供研讨会、试点项目计划和研究服务。研究：双相情感障碍（BD）是与物质使用障碍（SUD）最密切相关的I轴精神疾病；双相障碍和SUD同时发生与毁灭性的临床结果相关。研究表明，谷氨酸传递失调可能是SUD和BD共同发生的部分原因，直接或通过其对SUD和BD共同存在的神经行为缺陷的影响。尽管这一假设很有希望，但它是基于间接证据的，因为几乎没有涉及双相障碍和SUD共同发生的个体的神经影像学研究。拟议的研究将首次评估前扣带（ACC）谷氨酸、冲动性（反应抑制）和奖励敏感性（对酒精线索的敏感性）作为双相障碍和酒精依赖（AD）共病的因素，使用1H-MRS和fMRI对同时发生AD和心境型双相障碍、心境型双相障碍单独患者、心境型双相障碍单独患者和匹配的对照组进行评估。在Aim 1中，我们预测AD和BD共存的个体ACC谷氨酸（通过1H-MRS）与AD或BD单独存在的个体有显著不同。在aim 2中，我们预测，与单独患有AD或BD的个体相比，同时患有AD和BD的个体在被要求抑制阳性反应时，ACC/额叶（例如，右额叶下皮层）麸皮活动（通过fMRI Bold反应）明显更少。在Aim 3中，我们预测，与单独患有AD或BD的个体相比，同时患有AD和BD的个体在暴露于酒精提示时，其腹侧纹状体和ACC/额叶活动（通过fMRI）明显更大。对照受试者ACC谷氨酸水平最正常，ACC/额叶反应抑制活性水平最高，纹状体和额叶酒精提示活性水平最低，AD和BD之间的比较将是探索性的，因为这两组从未进行过比较。ACC谷氨酸（通过1H-MRS）、对酒精线索的神经激活（fMRI）和反应抑制（fMRI）与AD/BD诊断之间的关系将被探讨。该研究将为支持或反对谷氨酸神经传递作为AD和双相障碍共同发生的关键脑系统提供证据，并将为检验谷氨酸能药物治疗AD、BD和AD+双相障碍的机制作用提供范例。

DESCRIPTION (provided by applicant): Dr. Prisciandaro is a postdoctoral fellow in the Clinical Neuroscience Division (CND) of the Department of Psychiatry at the Medical University of South Carolina (MUSC); he will join the faculty as an Assistant Professor upon completion of his fellowship in July, 2012. Dr. Prisciandaro seeks a Mentored Patient-Oriented Research Career Development Award (K23), through the National Institutes of Health-National Institute on Alcohol Abuse and Alcoholism (NIH/NIAAA), to facilitate his career as an independent investigator conducting patient-oriented research in individuals with co-occurring alcohol use and bipolar disorders. Candidate: Dr. Prisciandaro is a clinical psychologist with extensive training in substance use and mood disorders research and practice, quantitative methods, and initial training in functional Magnetic Resonance Imaging (fMRI). His long-term career goal is to become an independent clinical scientist in the area of patient- oriented substance use and mood disorders research, with an emphasis on using neuroimaging to develop and test mechanistic models of co-occurring alcohol use and bipolar disorders. In order to realize this goal, Dr. Prisciandaro requires additional training. During the proposed award, Dr. Prisciandaro will 1) obtain sophisticated knowledge of the neurobiology of alcohol use and bipolar disorders, 2) learn how to design, conduct, and analyze fMRI and proton Magnetic Resonance Spectroscopy (1H-MRS) experiments to investigate the neurobiology of alcohol use and bipolar disorders, 3) augment existing clinical research skills, and 4) improve grantsmanship in order to successfully compete for an Independent Research Award (R01). Environment: MUSC ranks among the top 10 medical schools in the country for addiction education, and the MUSC College of Medicine has 7 departments ranked in the top 25 nationally in NIH funding including the Department of Psychiatry. Addictions collaborations span several departments and include 4 NIH center and 2 T32 addiction-research training grants. Across departments, over 30 faculty are engaged in addiction research; a number of these faculty will be mentors. Dr. Prisciandaro's proposed mentors/collaborators are international and national experts, including Drs. Raymond Anton, Jane Joseph, Truman Brown, Kathleen Brady, Mary Phillips (offsite), Alan Swann (offsite), Peter Kalivas, Hugh Myrick, and Bryan Tolliver. Study procedures will take place through the Clinical Neuroscience Division (CND). The CND (Dr. Brady-Director) will provide the infrastructure for the execution of the proposed research. Neuroimaging will be conducted at MUSC's Center for Advanced Imaging Research (CAIR; Dr. Brown-Director). CAIR's Siemens 3T Trio MRI, with integrated fMRI paradigm equipment, operates with a 100% mandate for research and is accompanied by comprehensive informatics support. Seminars, pilot project programs, and research services are further available through MUSC's Center for Drug and Alcohol Programs, Department of Neurosciences, South Carolina Clinical and Translational Research Institute, and Division of Biostatistics and Epidemiology. Research: Bipolar disorder (BD) is the Axis I psychiatric condition most strongly associated with substance use disorders (SUD); co-occurring BD and SUD are associated with devastating clinical outcomes. Research suggests that dysregulated glutamate transmission may be partially responsible for co-occurring SUD and BD, both directly and through its impact on neurobehavioral deficits that are common to both SUD and BD. Though promising, this hypothesis is based on indirect evidence, as there have been virtually no neuroimaging studies involving individuals with co-occurring BD and SUD. The proposed study will provide a first evaluation of anterior cingulate (ACC) glutamate, impulsivity (response inhibition), and reward sensitivity (sensitivity to alcohol cues) as contributors to comorbidity between BD and alcohol dependence (AD) using 1H-MRS and fMRI in individuals with co-occurring AD and euthymic BD, individuals with euthymic BD alone, individuals with AD alone, and a matched control group. In Aim 1, we predict that individuals with co-occurring AD and BD will have significantly different ACC glutamate (by 1H-MRS) relative to individuals with AD or BD alone.InAim 2, we predict that individuals with co-occurring AD and BD will demonstrate significantly less ACC/frontal (e.g., right inferior frontal cortex) bran activity (by fMRI Bold response) when asked to inhibit a prepotent response relative to individuals with AD or BD alone. In Aim 3, we predict that individuals with co- occurring AD and BD will have significantly greater ventral striatal and ACC/frontal activity (by fMRI) when exposed to alcohol cues relative to individuals with AD or BD alone. Control subjects are expected to have the most normal levels of ACC glutamate, highest levels of ACC/frontal activity to response inhibition, and lowest levels of striatal and frontal activity to alcohol cues Comparisons between AD and BD will be exploratory given that these groups have never been compared. The relationship between ACC glutamate (by 1H-MRS), neural activation to alcohol cues (fMRI) and response inhibition (fMRI), and AD/BD diagnosis will be explored. The proposed study will provide evidence for or against glutamate neurotransmission as a key brain system underlying co-occurring AD and BD, and will provide a paradigm for examining the mechanistic effects of glutamatergic drugs for the treatment of AD, BD, and AD+BD.