Neuromodulation of stress-induced dysfunction and drug-seeking in opioid use disorder: comparison of fronto-cortical targets

项目摘要/摘要 压力暴露可能会导致负面的生理和心理反应。压力会特别大 对于试图从阿片使用障碍(OUD)中恢复的人来说是个问题，因为它损害了执行功能 (EF)，并增加渴望和复发的可能性。申请人的赞助人(格林沃尔德博士)展示了 这种药理应激增加了寻求药物的行为；然而，应激的机制 对碰撞行为的认识还不够深入。此外，没有FDA批准的降低疗效的药物 对认知功能的压力和目前的OUD治疗不能有效地解决压力。这样做的目的是 培训项目是对申请者进行与物质使用有关的神经生物学机制的培训 在发展重复经颅磁刺激(RTMS)和 脑电技术。这些目标将通过扩大赞助商的工作来实现，以确定 背外侧前额叶皮质(DlPFC)和内侧前额叶皮质(MPFC)在调制中的作用 应激诱导的药物寻找，并研究这些靶点的调节如何改变应激诱导 认知和情感功能。RTMS的神经调节是一种很有前途的工具，可以开发出更深层次的 了解应激与药物相关结果的机制。相互竞争的神经行为 决策系统理论认为，患有肥胖症的人可能有过度活跃的边缘奖赏回路和 不活跃的执行控制电路；这一理论支持使用rTMS来瞄准边缘奖励(通过mPFC)或 执行控制(通过dlPFC)电路来调节药物寻找。使用混合设计，我们将检查 药物应激源(54 mg育亨宾+20 mg氢化可的松)与安慰剂(受试者内)的比较 与10 Hz dlPFC与Sham rTMS(组1)或1 Hz mPFC与Sham rTMS(组2)配合使用 参与者使用OUD。总体假设：通过dlPFC rTMS兴奋EF回路或抑制边缘 通过mPFC rTMS的回路将减轻应激诱导的执行功能障碍(目标1)或情绪调节障碍 (目标2)，分别相对于Sham。任一靶点的rTMS都将减弱应激诱导的阿片类药物寻求(AIM) 3)。实验设计、严谨和可重复的方法以及创新的假设都是基于 科学文献和来自赞助商实验室的强有力的初步和公开的数据。意义：这是 该项目将系统地促进对应激反应和药物的神经生物学机制的理解。 在OUD中使用，为将来的编程查询奠定了基础。未来可能的研究将评估： (1)刺激其他大脑结构以减少应激反应的作用；(2)使用脑成像和其他 生物标志物，以进一步探索这些干预的反应机制；以及(3)多个rTMS的影响 关于调整长期药物使用模式的会议。申请者已经建立了强大的导师关系 已经协作的团队，拥有与此项目相关的独特和交叉的专业知识，并将提供 达到她作为内科科学家的职业目标所必需的跨学科培训经验。

Project Summary/Abstract Stress-exposure may lead to negative physical and psychological responses. Stress can be especially problematic for people trying to recover from opioid use disorder (OUD) because it impairs executive function (EF) and increases craving and likelihood of relapse. The applicant’s Sponsor (Dr. Greenwald) demonstrated that pharmacological stress increases drug-seeking behavior; however, the mechanisms by which stress impacts behavior are not fully understood. Moreover, there are no FDA-approved medications to reduce effects of stress on cognitive function and current OUD treatments do not effectively address stress. The goals of this training project are to train the applicant in neurobiological mechanisms involved in substance use disorders (SUDs) while developing skills in repetitive transcranial magnetic stimulation (rTMS) and EEG techniques. These goals will be accomplished by expanding the Sponsor’s work to determine the roles of the dorsolateral prefrontal cortex (dlPFC) and medial prefrontal cortex (mPFC) in modulating stress-induced drug-seeking, and to investigate how modulation of these targets alters stress-induced cognitive and affective functions. Neuromodulation with rTMS is a promising tool for developing a deeper understanding of mechanisms relating stress to drug-related outcomes. The Competing Neurobehavioral Decisions System theory posits that persons with SUDs may have hyperactive limbic reward circuitry and hypoactive executive control circuitry; this theory supports using rTMS to target limbic reward (via mPFC) or executive control (via dlPFC) circuitry to modulate drug seeking. Using a mixed design, we will examine the effects of pharmacological stressor (54mg yohimbine + 20mg hydrocortisone) vs. placebo (within subject) in conjunction with either 10Hz dlPFC vs. sham rTMS (group 1) or 1Hz mPFC vs. sham rTMS (group 2) in participants with OUD. Overall hypothesis: Excitation of EF circuitry via dlPFC rTMS or inhibition of limbic circuitry via mPFC rTMS will attenuate stress-induced executive dysfunction (Aim 1) or emotional dysregulation (Aim 2), respectively, relative to sham. rTMS of either target will attenuate stress-induced opioid-seeking (Aim 3). The experimental design, rigorous and reproducible methods, and innovative hypotheses are based on scientific literature and strong preliminary and published data from the Sponsor’s lab. Significance: This project will systematically advance understanding of neurobiological mechanisms of stress-reactivity and drug use in OUD, forming the foundation for future programmatic inquiry. Potential future research would evaluate: (1) the role of stimulating other brain structures to reduce stress response; (2) use of brain imaging and other biomarkers to further explore mechanisms in response to these interventions; and (3) effects of multiple rTMS sessions on modulating longer-term patterns of drug use. The applicant has assembled a strong mentorship team who already collaborate, have unique and intersecting expertise relevant to this project, and will provide the interdisciplinary training experience necessary to meet her career goals as a physician-scientist.