Neuroimaging mechanisms of overlap between alcoholism and bipolar disorder

酗酒和双相情感障碍重叠的神经影像机制

• 批准号: 8382918
• 负责人: James Joseph Prisciandaro
• 金额: $ 17.03万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8382918
• 关键词: Acetylcysteine; Alcohol consumption; Alcohol dependence; Alcohol or Other Drugs use; Alcoholism; Alcohols; Anterior; Area; Award; Beverages; Biometry; Bipolar Disorder; Brain; Brain region; Clinical; Clinical Research; Collaborations; Comorbidity; Control Groups; Corpus striatum structure; Country; Development; Diagnosis; Diagnostic; Emotions; Environment; Epidemiology; Equipment; Evaluation; Event; Faculty; Fellowship; Functional Magnetic Resonance Imaging; Funding; Glutamatergic Agents; Glutamates; Goals; Grant; Health Care Costs; Human; Image; Impulsivity; Individual; Inferior; Informatics; International; Knowledge; Learning; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Medical; Medical Education; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Methods; Modeling; Mood Disorders; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Neurosciences; Outcome; Outcome Measure; Participant; Pharmaceutical Preparations; Pilot Projects; Population; Postdoctoral Fellow; Procedures; Protons; Psychiatry; Psychologist; Public Health; Regulation; Relative (related person); Research; Research Infrastructure; Research Institute; Research Personnel; Research Training; Resistance; Rewards; Scanning; Scientist; Services; Signal Transduction; South Carolina; Substance Use Disorder; System; Task Performances; Techniques; Testing; Training; Translational Research; United States National Institutes of Health; Universities; addiction; alcohol cue; alcohol exposure; alcohol sensitivity; base; behavior measurement; blood oxygen level dependent; career; college; craving; design; disorder control; effective therapy; executive function; frontal lobe; genetic variant; improved; medical schools; neural patterning; neurobehavioral; neurochemistry; neuroimaging; neurotransmission; new therapeutic target; non-alcoholic; patient oriented; patient oriented research; primary outcome; problem drinker; professor; programs; relating to nervous system; research study; response; skills; transmission process

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. PUBLIC HEALTH RELEVANCE: Bipolar Disorders (BD) and substance use disorders (SUD) co-occur very frequently, and co-occurring BD and SUD are associated with devastating public health costs. Unfortunately, there has been very little neurobiological research involving individuals with co-occurring BD and SUD to guide the development of effective treatments for this treatment-resistant population. In response to this clinical need, the proposed study will evaluate a potential mechanistic model of BD and alcohol dependence (AD) co-occurrence, involving shared neurochemical and neurobehavioral dysregulations, that could help to identify novel therapeutic targets for individuals with co-occurring BD and AD.

描述（由申请人提供）：Prisciandaro 博士是南卡罗来纳医科大学（MUSC）精神病学系临床神经科学部（CND）的博士后研究员； 2012 年 7 月完成奖学金后，他将作为助理教授加入该学院。Prisciandaro 博士通过美国国立卫生研究院-国家酒精滥用和酒精中毒研究所 (NIH/NIAAA) 寻求以患者为导向的研究职业发展奖 (K23)，以促进他作为独立研究者的职业生涯，对同时患有酒精使用和双相情感障碍的个体进行以患者为导向的研究。候选人：Prisciandaro 博士是一位临床心理学家，在物质使用和情绪障碍研究与实践、定量方法以及功能磁共振成像 (fMRI) 方面接受过广泛培训。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同时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，Prisciandaro 博士需要接受额外的培训。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、进行和分析功能磁共振成像和质子磁共振波谱 (1H-MRS) 实验，以研究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，4) 提高资助水平，以便 成功角逐独立研究奖（R01）。环境：MUSC 的成瘾教育医学院名列全国前 10 名，并且 MUSC 医学院有 7 个系在 NIH 资助中排名全国前 25 名，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 成瘾研究培训补助金。跨院系有 30 多名教职员工从事成瘾研究；其中一些教师将担任导师。 Prisciandaro 博士提议的导师/合作者是国际和国内专家，包括 Drs. Raymond Anton、Jane Joseph、Truman Brown、Kathleen Brady、Mary Phillips（场外）、Alan Swann（场外）、Peter Kalivas、Hugh Myrick 和 Bryan Tolliver。研究程序将通过临床神经科学部门（CND）进行。 CND（布雷迪博士主任）将为执行拟议研究提供基础设施。神经影像学将在 MUSC 高级影像研究中心（CAIR；布朗博士主任）进行。 CAIR 的西门子 3T Trio MRI 配有集成的 fMRI 范例设备，100% 负责研究任务，并配有全面的信息学支持。通过 MUSC 药物和酒精项目中心、神经科学系、南卡罗来纳州临床和转化研究所以及生物统计和流行病学部门，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) 相关性最强的 Axis I 精神疾病； BD 和 SUD 同时发生与破坏性的临床结果相关。研究表明，谷氨酸传输失调可能是 SUD 和 BD 共存的部分原因，既直接影响，也通过其对 SUD 和 BD 常见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，因为实际上还没有涉及同时患有 BD 和 SUD 的个体的神经影像学研究。拟议的研究将使用 1H-MRS 和 fMRI 对同时发生 AD 和正常 BD 的个体、仅患有正常 BD 的个体、仅患有 AD 的个体以及匹配的对照，对前扣带回 (ACC) 谷氨酸、冲动性（反应抑制）和奖赏敏感性（对酒精线索的敏感性）作为 BD 和酒精依赖 (AD) 合并症的影响因素进行首次评估 团体。在目标 1 中，我们预测同时发生 AD 和 BD 的个体与单独患有 AD 或 BD 的个体相比，其 ACC 谷氨酸（通过 1H-MRS）显着不同。在目标 2 中，我们预测当被要求抑制相对于 AD 个体的优势反应时，同时发生 AD 和 BD 的个体将表现出显着较低的 ACC/额叶（例如，右下额皮质）麸皮活性（通过 fMRI Bold 反应） 或单独BD。在目标 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线索时，腹侧纹状体和 ACC/额叶活动（通过 fMRI）显着更高。对照受试者预计具有最正常的 ACC 谷氨酸水平、最高水平的 ACC/额叶对反应抑制的活动以及最低水平的纹状体和额叶对酒精线索的活动。AD 和 BD 之间的比较将是探索性的，因为这些组从未进行过比较。将探讨 ACC 谷氨酸（通过 1H-MRS）、酒精线索神经激活 (fMRI) 和反应抑制 (fMRI) 以及 AD/BD 诊断之间的关系。拟议的研究将为支持或反对谷氨酸神经传递作为 AD 和 BD 共同发生的关键大脑系统提供证据，并将为检查谷氨酸药物治疗 AD、BD 和 AD+BD 的机制作用提供范例。 公共卫生相关性：双相情感障碍 (BD) 和物质使用障碍 (SUD) 经常同时发生，并且同时发生的 BD 和 SUD 会造成毁灭性的公共卫生成本。不幸的是，很少有神经生物学研究涉及同时患有 BD 和 SUD 的个体，以指导针对这种治疗抵抗人群开发有效的治疗方法。为了满足这一临床需求，拟议的研究将评估 BD 和酒精依赖 (AD) 共存的潜在机制模型，涉及共同的神经化学和神经行为失调，这可能有助于为同时发生 BD 和 AD 的个体确定新的治疗靶点。