Neuroimaging Abstinence and Medication Response

神经影像学戒断和药物反应

基本信息

批准号：
7612866
负责人：
CARYN LERMAN
金额：
$ 31.37万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7612866
关键词：
Abstinence Agonist Amygdaloid structure Anterior Back Behavioral Behavioral Mechanisms Biological Biostatistics Core Brain Brain region Candidate Disease Gene Cerebrovascular Circulation Clinical Code Cognitive Communities Crossover Design Data Development Dorsal Double-Blind Method Electrophysiology (science)Emotional Emotions Enrollment European Face Fingerprint Functional Magnetic Resonance Imaging Future Genes Genetic Crossing Over Genetic Polymorphism Genotype Goals Hippocampus (Brain)Human Image Insula of Reil Interdisciplinary Study Investigation Magnetic Resonance Imaging Measures Medial Mediating Methods Modeling Monitor Mus Nicotine Nicotine Dependence Nicotinic Receptors Nucleus Accumbens Outcome Participant Performance Perfusion Weighted MRI Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Pilot Projects Placebo Effect Placebos Prefrontal Cortex Procedures Process Proteins Reaction Time Regulation Relapse Research Research Design Rest Rewards Sampling Scanning Screening procedure Short-Term Memory Signal Transduction Smoke Smoker Smoking Speed Spin Labels Surrogate Markers Symptoms Task Performances Testing Ventral Striatum Work base behavioral pharmacology blood oxygen level dependent brain behavior cingulate cortex clinical efficacy data management data sharing emotional stimulus hedonic improved interest mouse model neuroimaging neuromechanism novel open label primary outcome relating to nervous system response satisfaction smoking cessation smoking relapse success varenicline

项目摘要

Abstinence from smoking produces aversive symptoms that prompt relapse, often within the first week following a quit attempt. Our prior work has characterized these nicotine abstinence symptoms in smoking cessation pharmacotherapy trials and identified those relating to smoking relapse. Extending this work, we propose to elucidate brain and behavioral mechanisms underlying medication effects on key early abstinence symptoms using arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI), and blood oxygen level dependent (BOLD) functional MRI (fMRI). Varenicline, an a4p2 nicotinic acetylcholine receptor partial agonist, will be used as a model medication, based on its superior clinical efficacy. The specific aims are: (1) to identify the neural substrates for varenicline effects on urges to smoke, using ASL perfusion MRI during a nicotine abstinent resting state, (2) To identify the neural substrates for varenicline effects on working memory during nicotine abstinence, using the N-back paradigm, and (3) To identify the neural substrates for varenicline effects on limbic reactivity to emotional stimuli during nicotine abstinence using a Face Emotion Identification fMRI paradigm. The study design is a within-subject double-blind crossover neuroimaging study of short-term (13 days) varenicline (vs. placebo) administration. Sixty treatmentseeking smokers will be scanned during 2 medication periods: (1) after 3 days of monitored abstinence while on varenicline, and (2) after 3 days of monitored abstinence while on placebo (medication order counterbalanced with a 2-week washout period). The primary outcomes are medication effects (within subject) on: (a) resting regional cerebral blood flow (rCBF) (ASL perfusion MRI), and (b) task-related BOLD activation (BOLD fMRI) after 3 days of abstinence. We will examine changes in behavioral performance and subjective symptoms in relation to brain activity changes. Following this investigation, all participants will be enrolled into a 12 week open-label varenicline trial, and we will explore associations of imaging data with clinical relapse. This research will contribute to pharmacotherapy development for nicotine dependence by: (a) providing a "neural fingerprint" against which future novel compounds can be compared, and (b) establishing the use neuroimaging as an early "surrogate marker" for medication response.

戒烟会产生厌恶症状，导致复吸，通常在第一周内尝试戒烟后。我们之前的工作已经描述了吸烟时的这些尼古丁戒断症状戒烟药物治疗试验并确定了与吸烟复发相关的试验。扩展这项工作，我们提议阐明药物对关键早期影响的大脑和行为机制使用动脉自旋标记 (ASL) 灌注磁共振成像 (MRI) 检测戒断症状，以及血氧水平依赖 (BOLD) 功能 MRI (fMRI)。 Varenicline，一种 a4p2 烟碱乙酰胆碱受体部分激动剂，基于其卓越的临床疗效，将被用作模型药物。这具体目标是：(1) 使用 ASL 确定伐尼克兰对吸烟冲动影响的神经底物尼古丁戒断静息状态下的灌注 MRI，(2) 识别伐尼克兰的神经底物使用 N-back 范式，在尼古丁戒断期间对工作记忆的影响，以及 (3) 确定伐尼克兰的神经底物对尼古丁戒断期间边缘系统对情绪刺激的反应的影响使用面部情绪识别功能磁共振成像范式。研究设计是受试者内双盲交叉短期（13 天）伐尼克兰（与安慰剂）给药的神经影像学研究。六十种治疗寻求吸烟者将在 2 个用药期间接受扫描：(1) 戒烟监测 3 天后，同时服用伐尼克兰，以及 (2) 在服用安慰剂期间监测戒酒 3 天后（用药顺序与 2 周的清洗期相平衡）。主要结局是药物效应（在主题）关于：（a）静息局部脑血流（rCBF）（ASL灌注MRI），和（b）任务相关的BOLD 禁欲 3 天后激活（BOLD fMRI）。我们将检查行为表现的变化和与大脑活动变化相关的主观症状。调查结束后，所有参与者都将参加了一项为期 12 周的开放标签伐尼克兰试验，我们将探讨影像数据与临床复发。这项研究将通过以下方式促进尼古丁依赖药物疗法的开发： (a) 提供“神经指纹”，可以与未来的新型化合物进行比较，以及 (b) 建立神经影像学作为药物反应的早期“替代标记”的用途。