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: 10610902
• 负责人: Tabitha Emily Howard Moses
• 金额: $ 5.27万
• 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/10610902
• 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; Collaborations; Data; Drug Modulation; 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; 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; Physicians; Placebos; Play; Prefrontal Cortex; Procedures; Protocols documentation; Public Health; Publishing; Relapse; Reproducibility; Research; Rewards; Role; Scientist; Site; Sorting; Stress; Structure; Substance Use Disorder; Systems Theory; Techniques; Training; Treatment Protocols; Wisconsin; Work; Yohimbine; acute stress; alpha-amylase; biological adaptation to stress; career; clinical translation; clinically significant; cognitive function; craving; design; drug seeking behavior; emotion dysregulation; executive function; experience; frontal lobe; human subject; improved; improved outcome; indexing; innovation; negative affect; neural; neurobehavioral; neurobiological mechanism; neuromechanism; neuropsychiatric disorder; neuroregulation; nicotine seeking behavior; opioid use; opioid use disorder; pharmacologic; psychologic; relapse risk; repetitive transcranial magnetic stimulation; response; reward circuitry; skills; stress management; stress reactivity; stress reduction; 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.

项目概要/摘要 压力暴露可能会导致负面的身体和心理反应。压力可能特别大 对于试图从阿片类药物使用障碍 (OUD) 中恢复的人来说是有问题的，因为它会损害执行功能 (EF) 并增加渴望和复发的可能性。申请人的担保人（格林沃尔德博士）证明 药物应激会增加寻求药物的行为；然而，压力的机制 影响行为尚未完全理解。此外，没有 FDA 批准的药物可以减少这种影响 压力对认知功能的影响和目前的 OUD 治疗并不能有效解决压力。本次活动的目标 培训项目旨在对申请人进行与药物使用有关的神经生物学机制方面的培训 疾病（SUD），同时培养重复经颅磁刺激（rTMS）和 脑电图技术。这些目标将通过扩大申办者的工作来实现，以确定 背外侧前额叶皮层 (dlPFC) 和内侧前额叶皮层 (mPFC) 在调节中的作用 压力诱导的药物寻求，并研究这些目标的调节如何改变压力诱导的药物寻求 认知和情感功能。 rTMS 神经调节是一种很有前途的工具，可用于开发更深层次的神经调节 了解压力与药物相关结果的相关机制。竞争性神经行为 决策系统理论认为，患有 SUD 的人可能具有过度活跃的边缘奖励回路，并且 执行控制电路功能低下；该理论支持使用 rTMS 来定位边缘奖励（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 毫克育亨宾 + 20 毫克氢化可的松）与安慰剂（受试者体内）的影响 与 10Hz dlPFC 与假 rTMS（第 1 组）或 1Hz mPFC 与假 rTMS（第 2 组）相结合 与 OUD 的参与者。总体假设：通过 dlPFC rTMS 激发 EF 电路或抑制边缘系统 通过 mPFC rTMS 的电路将减轻压力引起的执行功能障碍（目标 1）或情绪失调 （目标 2）分别相对于假手术。任一目标的 rTMS 都会减弱压力引起的阿片类药物寻求（Aim 3）。实验设计、严格且可重复的方法以及创新的假设均基于 来自申办者实验室的科学文献以及强有力的初步和已发表的数据。意义：这个 项目将系统地增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，为未来的程序化查询奠定了基础。未来潜在的研究将评估： (1)刺激大脑其他结构，减轻应激反应的作用； (2)利用脑成像等 生物标志物，以进一步探索响应这些干预措施的机制； (3) 多次 rTMS 的效果 关于调节长期药物使用模式的会议。申请人已集结了强大的导师 已经合作的团队，拥有与该项目相关的独特且交叉的专业知识，并将提供 实现她作为一名医师科学家的职业目标所必需的跨学科培训经验。

项目成果

Resolution of Selective Serotonin Reuptake Inhibitor-Associated Sexual Dysfunction After Switching From Fluvoxamine to Fluoxetine.

• DOI: 10.1097/jcp.0000000000001636
• 发表时间: 2023-01-01
• 期刊: JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY
• 影响因子: 2.9
• 作者: Moses, Tabitha E. H.;Javanbakht, Arash
• 通讯作者: Javanbakht, Arash

Effects of neuromodulation on cognitive and emotional responses to psychosocial stressors in healthy humans.

• DOI: 10.1016/j.ynstr.2023.100515
• 发表时间: 2023-01
• 期刊: NEUROBIOLOGY OF STRESS
• 影响因子: 5
• 作者: Moses, Tabitha E. H.;Gray, Elizabeth;Mischel, Nicholas;Greenwald, Mark K.
• 通讯作者: Greenwald, Mark K.

How Should Clinicians Determine a Traumatized Patient's Readiness to Return to Work?

• DOI: 10.1001/amajethics.2022.111
• 发表时间: 2022-02-01
• 期刊: AMA journal of ethics
• 作者: Moses TEH;Javanbakht A
• 通讯作者: Javanbakht A

Anhedonia modulates benzodiazepine and opioid demand among persons in treatment for opioid use disorder.

• DOI: 10.3389/fpsyt.2023.1103739
• 发表时间: 2023
• 期刊: FRONTIERS IN PSYCHIATRY
• 影响因子: 4.7
• 作者: Greenwald, Mark K. K.;Moses, Tabitha E. H.;Lundahl, Leslie H. H.;Roehrs, Timothy A. A.
• 通讯作者: Roehrs, Timothy A. A.

Developing and validating an opioid overdose prevention and response curriculum for undergraduate medical education.

• DOI: 10.1080/08897077.2021.1941515
• 发表时间: 2022
• 期刊: Substance abuse
• 影响因子: 3.5
• 作者: Moses TE;Moreno JL;Greenwald MK;Waineo E
• 通讯作者: Waineo E