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

阿片类药物使用障碍中应激引起的功能障碍和药物寻求的神经调节：额叶皮质目标的比较

• 批准号: 10388117
• 负责人: Tabitha Emily Howard Moses
• 金额: $ 4.52万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388117
• 关键词: Address; Affective; Arousal; Attenuated; Basic Science; Behavior; Behavioral; Biological Markers; Biological Models; Brain; Brain imaging; Brain region; Cigarette Smoker; Clinical Research; Cognitive; Data; Drug usage; Electroencephalography; Emotional; Event-Related Potentials; Executive Dysfunction; Experimental Designs; FDA approved; Foundations; Functional disorder; Future; Goals; Heart Rate; Hydrocortisone; Hyperactivity; Impairment; Individual; Intervention; Knowledge; Lead; Learning; Left; Literature; Location; Major Depressive Disorder; Measurement; Measures; Medial; Mentorship; Methods; Modeling; Motivation; National Institute of Drug Abuse; Neurobiology; Opioid; Outcome; Participant; Pathway interactions; Pattern; Persons; Pharmaceutical Preparations; Pharmacology; Physicians; Placebos; Play; Prefrontal Cortex; Procedures; Protocols documentation; Public Health; Publishing; Relapse; Reproducibility; Research; Rewards; Role; Scientist; Site; Sorting - Cell Movement; Stress; Structure; Substance Use Disorder; Systems Theory; Techniques; Training; Treatment Protocols; Wisconsin; Work; Yohimbine; acute stress; alpha-amylase; base; biological adaptation to stress; career; clinically significant; cognitive function; craving; design; drug seeking behavior; emotion dysregulation; executive function; experience; human subject; improved; improved outcome; indexing; innovation; negative affect; neurobehavioral; neurobiological mechanism; neuromechanism; neuropsychiatric disorder; neuroregulation; nicotine seeking behavior; opioid use; opioid use disorder; psychologic; relapse risk; relating to nervous system; repetitive transcranial magnetic stimulation; response; reward circuitry; skills; stress management; stress reactivity; stressor; substance use; theories; therapeutically effective; therapy development; tool; training project

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.

项目总结/摘要 压力暴露可能导致消极的生理和心理反应。压力可能特别 对于试图从阿片类药物使用障碍（OUD）中恢复的人来说， (EF)并增加渴望和复发的可能性。申请人的申办者（Dr. Greenwald）证明 药理学压力会增加药物寻求行为;然而，压力的机制 影响行为还不完全清楚。此外，没有FDA批准的药物来减少影响， 压力对认知功能的影响，目前的OUD治疗不能有效地解决压力。这个的目标 培训项目是对申请人进行有关物质使用的神经生物学机制的培训 在重复经颅磁刺激（rTMS）中发展技能的同时， 脑电图技术。这些目标将通过扩大申办者的工作来实现， 背外侧前额叶皮层（dlPFC）和内侧前额叶皮层（mPFC）在调节 应激诱导的药物寻求，并研究这些目标的调节如何改变应激诱导的 认知和情感功能。使用rTMS的神经调节是一种有前途的工具， 了解压力与药物相关结果的相关机制。竞争的神经行为 决策系统理论认为，SUD患者可能有过度活跃的边缘系统奖励回路， 执行控制回路功能减退;该理论支持使用rTMS来靶向边缘系统奖励（通过mPFC），或 执行控制（通过dlPFC）电路来调节药物寻求。使用混合设计，我们将检查 药理学应激物（54 mg育亨宾+20 mg氢化可的松）与安慰剂（受试者内）对 联合10 Hz dlPFC与假rTMS（组1）或1 Hz mPFC与假rTMS（组2）， 参与者OUD。总体假设：通过dlPFC rTMS激发EF回路或抑制边缘系统 通过mPFC rTMS的回路将减弱应激诱导的执行功能障碍（Aim 1）或情绪失调 (Aim 2），分别相对于假手术。任一靶点的rTMS将减弱应激诱导的阿片样物质寻求（Aim 3）。实验设计，严谨和可重复的方法，以及创新的假设是基于 科学文献以及申办方实验室的有力初步和已发表数据。意义：这 该项目将系统地推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，为未来的程序化调查奠定基础。未来可能的研究将评价： (1)刺激其他大脑结构以减少应激反应的作用;（2）使用大脑成像和其他 生物标志物，以进一步探索这些干预措施的机制;（3）多种rTMS的影响 关于调整长期吸毒模式的会议。申请人已经组建了一个强大的导师队伍 团队已经合作，具有与此项目相关独特和交叉专业知识，并将提供 必要的跨学科培训经验，以满足她的职业目标作为一个医生，科学家。