Ventral Prefrontal Network Connectivity and Alcohol Sensitivity in Bipolar Disorder and Typically Developing Young Adults

项目摘要 这位露丝·L Kirschstein博士前个人国家研究奖描述了一个研究和培训 该计划将为申请人Dylan Kirsch作为独立研究科学家的职业生涯做好准备， 精神疾病在酒精使用障碍中的作用拟议的研究计划将测试神经生物学 导致双相情感障碍患者对酒精敏感性改变的机制， 成年人了对酒精的主观反应差异可预测酒精使用问题和酒精使用风险 通常发育中的青少年的疾病，然而，导致这种风险的机制-或如果类似 精神疾病的发病机制尚不清楚。我们将检验结构性的假设 腹侧前额叶皮层网络的连通性与酒精诱导的网络功能变化有关 连接性，以及对酒精的主观敏感性。该项目的结果有可能为 我们对双相情感障碍患者酒精使用障碍风险的神经生物学机制的理解 通常是发育中的年轻人。申请人和导师伊丽莎白·利帕德博士和金博士 弗罗姆设计了一个全面的研究和培训计划来验证这一假设。培训计划 强调1）在双相和酒精的神经生物学机制和临床问题的概念培训 使用障碍; 2）高级神经成像（功能连接和弥散张量）的方法学培训 成像[DTI]方法学）和安慰剂对照的酒精给药;和3）职业发展技能， 包括指导，统计，教学，写作和负责任的研究行为。研究目的：（1） 确定腹侧前额叶网络功能连接的变化是否对酒精产生反应， 情感处理-在双相情感障碍中是不同的，与典型的年轻人相比，如果 酒精引起的这些网络内功能连接的变化与对酒精的主观反应有关; 以及2）如果腹侧前额叶网络内的结构连接与对酒精的主观反应有关， 酒精引起的功能连接的变化。患有双相情感障碍的年轻人（21-26岁）， 发育对照组（每组n=30）将在基线时完成DTI，在安慰剂对照组期间完成功能MRI。 实验室酒精给药阶段（受试者内，平衡）。我们预测酒精会减弱 腹侧前额叶网络的功能连接，并且双相情感障碍者的变化幅度较小。 与对照组相比，与较低的主观反应相关的变化幅度较小， 酒精我们预测，较弱的结构连接将与较低的主观反应酒精和较小的 两组中酒精诱导的功能连接变化。研究结果将有助于我们了解 这些过程导致了对酒精敏感性的差异，并提出了一种神经生物学机制， 有助于对酒精的敏感性和酒精使用障碍的风险。该奖学金对申请人至关重要 追求她的培训目标，测试假设，并朝着她的研究生涯的下一个阶段的进展。

PROJECT ABSTRACT This Ruth L. Kirschstein PreDoctoral Individual National Research Award describes a research and training program that will prepare the applicant, Dylan Kirsch, for a career as an independent research scientist focused on the role of psychiatric illness in alcohol use disorders. The proposed research plan will test neurobiological mechanisms that contribute to altered sensitivity to alcohol in bipolar disorder and typically developing young adults. Differences in subjective response to alcohol predict alcohol use problems and risk for alcohol use disorders in typically developing youth, however the mechanisms that contribute to this risk—or if similar mechanisms are observed—in psychiatric illness are unclear. We will test the hypothesis that structural connectivity within ventral prefrontal cortical networks is related to alcohol-induced changes in network functional connectivity, and therefore, subjective sensitivity to alcohol. Results from the project have the potential to inform our understanding of neurobiological mechanisms that contribute to risk for alcohol use disorders in bipolar disorder and typically developing young adults. The applicant and mentors, Drs. Elizabeth Lippard and Kim Fromme have designed a comprehensive research and training plan to test this hypothesis. The training plan emphasizes 1) conceptual training in the neurobiological mechanisms and clinical issues in bipolar and alcohol use disorders; 2) methodological training in advanced neuroimaging (functional connectivity and diffusion tensor imaging [DTI] methodology) and placebo-controlled alcohol administration; and 3) career development skills, including mentorship, statistics, teaching, writing, and responsible conduct of research. Research aims are to 1) determine if changes in ventral prefrontal network functional connectivity in response to alcohol—during emotional processing—are different in bipolar disorder, compared to typically developing young adults, and if alcohol-induced changes in functional connectivity within these networks relate to subjective response to alcohol; and 2) if structural connectivity within ventral prefrontal networks relates to subjective response to alcohol and alcohol-induced changes in functional connectivity. Young adults (ages 21-26) with bipolar disorder and typically developing controls (n=30 per group) will complete DTI at baseline and functional MRI during placebo-controlled laboratory alcohol administration sessions (within subject, counter-balanced). We predict alcohol will weaken functional connectivity in the ventral prefrontal network and that magnitude of change will be smaller in bipolar disorder, compared to controls, with smaller magnitude of change associated with lower subjective response to alcohol. We predict weaker structural connectivity will relate to lower subjective response to alcohol and smaller alcohol-induced changes in functional connectivity in both groups. Findings will aid in our understanding of the processes that contribute to differences in sensitivity to alcohol and suggest a neurobiological mechanism that contributes to sensitivity to alcohol and risk for alcohol use disorders. This fellowship is critical for the applicant to pursue her training objectives, test the hypothesis, and progress towards the next stage of her research career.