fMRI Study of Motivation, Decision-Making, Reward, Risk, Aversion, Craving, impulsivity, and Stress in Alcohol Use Disorders

酒精使用障碍中的动机、决策、奖励、风险、厌恶、渴望、冲动和压力的功能磁共振成像研究

• 批准号: 9559243
• 负责人: Abdolreza Momenan
• 金额: $ 66.65万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9559243
• 关键词: Adult; Affect; Alcohol consumption; Alcohol dependence; Alcoholic beverage heavy drinker; Alcohols; Amygdaloid structure; Anterior; Area Under Curve; Attention deficit hyperactivity disorder; Behavioral; Beverages; Bilateral; Biology; Brain; Clinical; Collaborations; Corpus striatum structure; Corticotropin-Releasing Hormone Receptors; Cues; Data; Data Analyses; Decision Making; Dopamine; Emotional; Enrollment; Extinction (Psychology); Face; Feedback; Food; Fright; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Transcription; Genomics; Goals; Heavy Drinking; Human; Hunger; Image; Image Analysis; Impairment; Impulsivity; Incentives; Individual; Inferior; Infusion procedures; Insula of Reil; Intravenous; Investigational Therapies; Journals; Left; Life Stress; Light; Manuscripts; Medial; Mediator of activation protein; Methylation; Modification; Molecular; Motivation; Neurons; Neuropeptides; Neurosciences; Nucleus Accumbens; Nutritional; Omega-3 Fatty Acids; Participant; Patients; Perception; Pharmaceutical Preparations; Placebos; Play; Population; Preparation; Procedures; Psychiatry; Psychoneuroendocrinology; Publications; Resistance; Rest; Rewards; Risk; Role; Self Administration; Shock; Signal Transduction; Stress; Supplementation; Testing; addiction; alcohol abuse therapy; alcohol craving; alcohol cue; alcohol effect; alcohol reward; alcohol seeking behavior; alcohol use disorder; breath alcohol measurement; caudate nucleus; conditioned fear; craving; cue reactivity; design; dopamine transporter; ghrelin; insight; meetings; neural correlate; neuroimaging; neuropsychopharmacology; novel; power analysis; relating to nervous system; response; reuptake; reward anticipation; reward circuitry; reward processing; translational study; trend

1. fMRI Studies of Motivation a. Dopamine Transporter Methylation and Reward Anticipation. In collaboration with Dr. Falk Lohoffs Section on Clinical Genomics and Experimental Therapeutics (CGET), and Dr. Nora Volkows Laboratotry of Neuroimaging (LNI), we analyzed Monetary Incentive Delay (MID) task data to investigate if there was an effect of SLC6A3 methylation on reward processing. We found that percent methylation of SLC6A3 significantly predicted reward anticipation-related activity in the caudate and nucleus accumbens in alcohol dependent patients but not in healthy control individuals. Higher methylation may result in lower DAT transcription and expression in the striatum, which may in turn compromise dopamine reuptake. Compromised dopamine reuptake may impair decision-making associated with excess drug seeking. We have submitted a manuscript: Dopamine Transporter Gene Methylation is Associated with Nucleus Accumbens Activation during Reward Processing in Healthy but not Alcohol-Dependent Individuals, to the journal of Addiction Biology that is under review. We are currently working on the potential effects this factor may have on the on the neural substrates of viewing emotional faces. b. MID Task for Neuroimaging Omega-3 and Reward in Adults with ADHD (NORAA) trial Study. A modified version of the MID task was used in a collaboration with Dr. Hibbeln of the Section on Nutritional Neuroscience. In this study, the effect of Omega-3 supplementation on reward circuitry was investigated in a population of adults with ADHD. CNIRC has assisted in the design and conducted the analysis of this component of the study. Potential differences in reward processing in individuals with ADHD has been observed. Detailed analysis of the data and preparation of the manuscript are underway. c. Reward Incentive Delay (RID) Task for Ghrelin Study. We analyzed the data from a study conducted by Dr. Leggios Section on Clinical Psychoneuroendocrinology and Neuropsychopharma-cology (CPN). This study used the RIDfb task, a modification of the MID task that uses food and beverage images as cues, to investigate the role of ghrelin, a neuropeptide involved in regulating hunger and reward perception, in alcohol craving and use in a population of non-treatment seeking heavy drinkers. In this task, the neural regions associated with motivation and response to reward were assessed as the participants attempted to earn points for intravenous alcohol and food rewards. Results showed that ghrelin increased the alcohol-cue signal in the amygdala and modulated the food-cue signal in the medial orbitofrontal cortex and nucleus accumbens. We also found increased resting-state connectivity between right amygdala and right mOFC prior to alcohol infusion and decrease connectivity after the alcohol infusion. The relationship between breath alcohol concentration and subjective effects of alcohol was also moderated by ghrelin. These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder. The manuscript for this study: Exogenous Ghrelin Administration Increases Alcohol Self-Administration and Modulates Brain Functional Activity in Heavy-Drinking Alcohol-Dependent Individuals has been accepted for publication in Molecular Psychiatry. d. Reward Incentive Delay with Shock (RIDs) Task. We have continued conducting a novel translational study to explore the neural correlates of aversion resistant alcohol addiction using a paradigm, which adds an aversive component to the RID task. In this study, the participants (light and heavy drinkers) are able to earn points for real alcohol and food rewards at the risk of receiving a small electric shock. The behavioral results indicate a difference between light and heavy drinkers for high threat alcohol. Heavy drinkers are more willing to risk receiving an electric shock in order to win alcohol points, indicated by a greater number of button presses during high threat alcohol trials. Our neuroimaging results indicate that heavy drinkers have increased amygdala activation when participants see an alcohol cue in the high threat condition compared to light drinkers. Heavy drinkers show increased BOLD activation in the striatum and insula during alcohol miss feedback compared to light drinkers. This increase in activation may represent a prediction error signal, which is higher in the heavy drinkers due to the increased salience of the alcohol reward to this group. We are currently enrolling the last few subjects needed to complete this study. 2. fMRI Studies of Decision-Making Ultimatum Task. We have conducted a study utilizing a modified version of the Ultimatum Game, a paradigm where participants are given an offer which divides $20.00 between the participant and the proposer. Participants were given the option to accept or reject each offer. Previous studies have demonstrated that the insula plays a key role in processing perceived unfair offers. Our fMRI results indicate higher activation in the healthy controls (HCs) compared to alcohol dependent inviduals in the insular cortex to unfair offers (less than $15:$5 split) that were later rejected. HCs insula activation may have acted as a mediator between emotional responses versus the risk of rejecting such offers. The manuscript for this study is under review. 3. fMRI Studies of Stress In a collaborative study with Dr. Lohoffs CGET we have implemented an fMRI fear extinction task. The primary goal of this study is to evaluate the role and interaction of (epi)genetic factors, early life stress (ELS) exposure, and alcohol use disorder (AUD) on neuronal mechanisms of fear conditioning and extinction. We have completed the preliminary analysis of the imaging data for 54 participants. Having found some trend level hypothesized neural responses, it has been decided that the study will continue collecting data to increase the statistical power of analyses. 4. Experimental fMRI Studies and Treatments a. GSK Study. We provided the imaging expertise for an experimental treatment study investigating verucerfont (CRF receptor antagonist) as a potential treatment for participants with alcohol use disorders (Schwandt, Cortes et al. 2016). The imaging results not only showed significant effects of the verucerfont, but also suggested that the CRF receptor antagonist may have a the motivational effect on alcohol cue reactivity. We tested this hypothesis by conducting an analysis of functional connectivity. We have presented the results of this analysis at the 2017 RSA meeting. We found that compared to placebo group, the verucerfont group showed reduction of the connectivity of the bilateral CeM with regions of the mPFC, dorsolateral PFC, IFG, and anterior insula when viewing alcohol vs. non-alcohol pictures. Additionally, the Verucerfont group showed a trend towards a positive correlation between the task-driven connectivity of the left CeMA with the bilateral superior frontal gyri/SMA and the area under the curve of the AUQ scores during the neutral script. These findings may provide insight into the lack of behavioral difference between the two groups in reducing the alcohol craving by verucerfont. b. BMS Trier Data Analysis. We have further analyzed the imaging data of the Trier test, a stress inducing procedure, collected during a previous study of Pexacerfont (Kwako et al. 2015). Our preliminary analyses indicate increased activation in the anterior cingulate and inferior frontal gyri in alcohol dependent patients when listening to self-referential stress scripts compared to non-self stress scripts. These differences were reduced in individuals who were treated with Pexacerfont but did not reachstatistical significance. The data is still under analysis.

1. 动机的功能磁共振成像研究 一个。多巴胺转运蛋白甲基化和奖励预期。我们与 Falk Lohoffs 博士临床基因组学和实验治疗学部门 (CGET) 以及 Nora Volkows 神经影像实验室 (LNI) 博士合作，分析了货币激励延迟 (MID) 任务数据，以调查 SLC6A3 甲基化是否存在影响关于奖励处理。我们发现，SLC6A3 的甲基化百分比可以显着预测酒精依赖患者尾状核和伏核中奖励预期相关的活动，但不能预测健康对照个体的奖励预期相关活动。较高的甲基化可能导致纹状体中 DAT 转录和表达较低，进而可能损害多巴胺再摄取。多巴胺再摄取受损可能会损害与过度寻求药物相关的决策。我们已向《成瘾生物学》杂志提交了一份手稿：多巴胺转运蛋白基因甲基化与健康但不依赖酒精的个体的奖励处理过程中的伏隔核激活有关，该杂志正在接受审查。我们目前正在研究这个因素可能对观看情绪面孔的神经基础产生的潜在影响。 b.成人 ADHD 神经影像 Omega-3 和奖励 (NORAA) 试验研究的 MID 任务。与营养神经科学部门的 Hibbeln 博士合作使用了 MID 任务的修改版本。在这项研究中，在患有多动症的成年人群中调查了补充 Omega-3 对奖赏回路的影响。 CNIRC 协助设计并进行了该研究的这一部分的分析。已经观察到多动症患者奖励处理的潜在差异。数据的详细分析和手稿的准备工作正在进行中。 c. Ghrelin 研究的奖励激励延迟 (RID) 任务。我们分析了 Leggios 博士临床心理神经内分泌学和神经精神药理学 (CPN) 部门进行的一项研究的数据。这项研究使用 RIDfb 任务（MID 任务的改进版，使用食物和饮料图像作为线索）来研究生长素释放肽（一种参与调节饥饿和奖赏感知的神经肽）在非酒精人群中对酒精渴望和使用的作用。寻求酗酒者的治疗。在这项任务中，当参与者试图通过静脉注射酒精和食物奖励来赚取积分时，对与动机和奖励反应相关的神经区域进行了评估。结果表明，生长素释放肽增加了杏仁核中的酒精提示信号，并调节了内侧眶额皮质和伏隔核中的食物提示信号。我们还发现，在输注酒精之前，右侧杏仁核和右侧 mOFC 之间的静息态连接性增加，而在输注酒精后，连接性降低。呼吸酒精浓度与酒精主观影响之间的关系也受到胃饥饿素的调节。这些数据表明，生长素释放肽信号传导会影响人类对酒精的寻求，应该作为开发治疗酒精使用障碍的新药物的有希望的目标进行进一步研究。这项研究的手稿：外源性生长素释放肽管理增加酒精自我管理并调节重度饮酒酒精依赖个体的大脑功能活动已被《分子精神病学》接受发表。 d.奖励激励延迟与休克 (RID) 任务。我们继续进行一项新颖的转化研究，使用范式探索厌恶性酒精成瘾的神经相关性，该范式在 RID 任务中添加了厌恶成分。在这项研究中，参与者（轻度和重度饮酒者）能够冒着受到轻微电击的风险，获得真正的酒精和食物奖励积分。行为结果表明轻度饮酒者和重度饮酒者在高威胁酒精方面存在差异。酗酒者更愿意冒着被电击的风险来赢得酒精分数，这一点可以从高威胁酒精试验中按下按钮的次数增多看出。我们的神经影像学结果表明，与轻度饮酒者相比，当参与者在高威胁条件下看到酒精提示时，重度饮酒者的杏仁核激活增加。与少量饮酒者相比，大量饮酒者在酒精错过反馈期间纹状体和岛叶的 BOLD 激活增加。这种激活的增加可能代表了一个预测误差信号，由于酒精奖励对该群体的显着性增加，该信号在重度饮酒者中更高。我们目前正在招募完成这项研究所需的最后几名受试者。 2. 决策的功能磁共振成像研究 最后通牒任务。我们利用最后通牒博弈的修改版本进行了一项研究，在该范例中，参与者获得报价，在参与者和提议者之间分配 20.00 美元。参与者可以选择接受或拒绝每个提议。先前的研究表明，脑岛在处理感知到的不公平报价方面发挥着关键作用。我们的功能磁共振成像结果表明，与酒精依赖者相比，健康对照组 (HC) 的岛叶皮质对不公平报价（低于 15 美元：5 美元的分配）的激活程度更高，但随后被拒绝。 HC 岛叶激活可能在情绪反应与拒绝此类提议的风险之间发挥中介作用。这项研究的手稿正在审查中。 3. 压力的功能磁共振成像研究 在与 Lohoffs CGET 博士的合作研究中，我们实施了一项 fMRI 恐惧消除任务。本研究的主要目标是评估（表观）遗传因素、早期生活压力（ELS）暴露和酒精使用障碍（AUD）对恐惧调节和消退的神经元机制的作用和相互作用。我们已经完成了 54 名参与者的影像数据的初步分析。在发现了一些趋势水平假设的神经反应后，我们决定该研究将继续收集数据以提高分析的统计能力。 4. 实验性功能磁共振成像研究和治疗 一个。葛兰素史克研究。我们为一项实验性治疗研究提供了成像专业知识，该研究调查了 verucerfont（CRF 受体拮抗剂）作为酒精使用障碍参与者的潜在治疗方法（Schwandt、Cortes 等人，2016 年）。成像结果不仅显示了verucerfont的显着效果，而且还表明CRF受体拮抗剂可能对酒精提示反应性具有激励作用。我们通过功能连接分析来检验这一假设。我们已在 2017 年 RSA 会议上展示了这一分析结果。我们发现，与安慰剂组相比，verucerfont 组在观看酒精图片和非酒精图片时，双侧 CeM 与 mPFC、背外侧 PFC、IFG 和前岛叶区域的连接性降低。此外，Verucerfont 组显示出左 CeMA 与双侧额上回/SMA 的任务驱动连接与中性脚本期间 AUQ 分数曲线下面积之间呈正相关的趋势。这些发现可能有助于了解两组在减少酒精渴望方面缺乏行为差异。 b. BMS 特里尔数据分析。我们进一步分析了 Trier 测试的成像数据，Trier 测试是一种压力诱导程序，是在之前的 Pexacerfont 研究中收集的（Kwako 等人，2015 年）。我们的初步分析表明，与非自我压力脚本相比，酒精依赖患者在聆听自我参照压力脚本时，前扣带回和额下回的激活增加。在接受 Pexacerfont 治疗的个体中，这些差异有所减少，但没有达到统计学意义。数据仍在分析中。