Identifying Electrophysiological Targets for Transcranial Magnetic Stimulation in Cocaine Use Disorder

项目摘要 目前迫切需要确定可卡因使用障碍（CUD）的新治疗靶点， 治疗基本上失败了。该奖项的目的是评估经颅磁共振成像的效果。 刺激（TMS）对成人CUD患者奖励功能的脑电图（EEG）标记物的影响。这一目标 韦伯博士的研究战略和严格的培训计划将满足这一要求，韦伯博士具有独特的地位， 利用脑电图评估TMS对CUD脑的影响。基于韦伯博士的专业知识， 认知神经科学，电生理学和成瘾，目前的职业发展计划将提供 培训：1）经颅磁刺激研究和临床应用，2）高级时频- 基于脑电图分析的方法，以及3）运行独立的临床试验。本次培训 将把韦伯博士在TMS开发和机制识别的最前沿的物质使用 并将韦伯博士定位为成瘾神经科学的独立研究者。虽然TMS 已经显示出治疗CUD的早期成功，但优化TMS存在重要但可解决的问题 治疗首先，大多数研究都刺激了背外侧前额叶皮层，但大脑中的许多区域都没有刺激。 前额叶皮层在长期可卡因使用中是活动减退的其次，确定可靠的生物标志物至关重要， 在临床试验中确定治疗目标和替代终点。电生理标记（奖励 积极性和迟发性正电位）的奖励敏感性和对药物线索的动机性注意，两个 阻碍治疗成功和增加复发风险的因素，为TMS操作带来了希望。第三、 TMS效应的异质性仍然需要解释，这可能导致个体化的改善。 治疗目前的研究将比较一个新的部位，背内侧前额叶皮层， 传统的背外侧前额叶皮层在3臂，受试者内，交叉设计，以评估急性 TMS管理对奖励积极性和后期积极潜力的影响。这个概念验证研究 将提供关于TMS管理是否有可能操纵重要奖励的关键信息 在CUD中观察到功能缺陷。这将通过以下方式实现：1）评估TMS对 与假手术相比，背内侧前额叶皮质和左背外侧前额叶皮质的时间-频率 2）评估TMS对背内侧前额叶皮层和左额叶皮层的影响， 背外侧前额叶皮层与假手术相比的晚正电位，以及3）识别个体 TMS效应与基线特征（CUD严重程度，冲动性和渴望）的差异。这项工作将 有助于增加CUD中TMS的知识，并为设计和 在K 01培训的第5年提交R 01申请，从而启动Webber博士的课程 走向独立的研究生涯。最终，这项工作将导致最佳大脑的发展 刺激程序，以治疗CUD和其他物质使用障碍。

PROJECT SUMMARY There is an urgent need to identify novel treatment targets for cocaine use disorder (CUD), as pharmacological treatments have largely failed. The goal of this award is to evaluate the effects of transcranial magnetic stimulation (TMS) on electroencephalogram (EEG) markers of reward functioning in adults with CUD. This goal will be met by the research strategy and a rigorous training plan for Dr. Webber, who is uniquely positioned to utilize electroencephalogram to assess TMS effects on the brain in CUD. Building on Dr. Webber's expertise in cognitive neuroscience, electrophysiology, and addiction, the current career development plan will provide training in: 1) transcranial magnetic stimulation research and clinical application, 2) advanced time-frequency- based approach to electroencephalogram analysis, and 3) running an independent clinical trial. This training will put Dr. Webber at the forefront of TMS development and mechanism identification for substance use disorders and will position Dr. Webber as an independent investigator in addiction neuroscience. While TMS has shown early success for treating CUD, there are important, yet addressable issues for optimizing TMS treatment. First, the majority of studies have stimulated dorsolateral prefrontal cortex, yet many areas of the prefrontal cortex are hypoactive in chronic cocaine use. Second, it is vital to identify reliable biomarkers to identify targets for treatment and alternative end points in clinical trials. Electrophysiological markers (Reward Positivity and Late Positive Potential) of reward sensitivity and motivated attention toward drug cues, two factors that hinder treatment success and increase risk for relapse, hold promise for TMS manipulation. Third, heterogeneity in TMS effects still need to be explained, which can lead to the improvement of individualized treatment. The current study will compare a novel site, dorsomedial prefrontal cortex, to both sham and traditional dorsolateral prefrontal cortex in a 3-arm, within-subjects, cross-over design to assess the acute effects of TMS administration on the Reward Positivity and Late Positive Potential. This proof-of-concept study will provide critical information on whether TMS administration has the potential to manipulate important reward functioning deficits observed in CUD. This will be accomplished by: 1) Assessing the effects of TMS to the dorsomedial prefrontal cortex and left dorsolateral prefrontal cortex compared to sham on the time-frequency aspects of the Reward Positivity, 2) Assessing the effects of TMS to the dorsomedial prefrontal cortex and left dorsolateral prefrontal cortex compared to sham on the Late Positive Potential, and 3) Identifying individual differences in TMS effects with baseline characteristics (CUD severity, impulsivity, and craving). This work will contribute to increasing knowledge of TMS in CUD and provide a strong foundation for the design and submission of an R01 application in Year 5 of the K01 training, thereby launching Dr. Webber's progression toward an independent research career. Ultimately, this work will lead to the development of optimal brain stimulation procedures to treat CUD and other substance use disorders.