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: 9155428
• 负责人: Abdolreza Momenan
• 金额: $ 140.15万
• 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/9155428
• 关键词: Adult; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcoholic beverage heavy drinker; Alcoholism; Alcohols; Alleles; Amygdaloid structure; Attention deficit hyperactivity disorder; Aversive Stimulus; Behavior; Behavioral; Brain; Collaborations; Conflict (Psychology); Corpus striatum structure; Corticotropin-Releasing Hormone Receptors; Cues; Data; Decision Making; Dorsal; Emotional; Enrollment; Exhibits; Extinction (Psychology); Face; Feedback; Food; Functional Magnetic Resonance Imaging; Genetic Variation; Genotype; Globus Pallidus; Hormones; Human; Hunger; Image; Impulsivity; Incentives; Individual; Insula of Reil; Lesion; Light; Magnetic Resonance; Measures; Mediator of activation protein; Motivation; Naltrexone; Neuropeptides; Nicotinic Receptors; Notification; Omega-3 Fatty Acids; Outcome; Participant; Patients; Perception; Performance; Pharmaceutical Preparations; Phase; Pilot Projects; Placebos; Play; Population; Post-Traumatic Stress Disorders; Process; Property; Research Design; Resistance; Rewards; Risk; Risk-Taking; Role; Scanning; Shock; Signal Transduction; Stress; Substance P; Substance P Receptor; Syndrome; System; Time; Update; Ventral Striatum; addiction; alcohol craving; alcohol cue; alcohol reward; alcohol use disorder; anxious; aprepitant; base; blood oxygenation level dependent response; craving; drinking; drug craving; drug relapse; experience; ghrelin; glucagon-like peptide; help-seeking behavior; high reward; indexing; motivational processes; neural correlate; novel; relating to nervous system; response; reward processing; risk variant; tool; translational study; varenicline

1. fMRI Studies of Motivation a. MID and GLP1R. As part of an collaboration with Dr. Leggio, we carried out an analysis of fMRI data in ADPs who completed the MID task. SBEIs role was to explore the association of genetic variations of GLP1R in alcohol dependent participants brain activations (Suchankova et al., 2015). The hormone glucagon-like peptide-1 (GLP-1) is involved in reward processing. There was a significant difference in brain activation in the right globus pallidus when contrasting the genotypes for the rs6923761 SNP. ADPs carrying the non-risk allele displayed lower BOLD response in the right globus pallidus than those carrying the risk allele when receiving notification of outcome for high reward. This finding indicates that individuals with the risk allele may have a dysfunctional reward system. b. MID and Varenicline. SBEI has created a modified version of the MID task, which uses naturalistic rewards such as food and alcohol, in place of monetary reward. This task is referred to as reward incentive delay (RID). Dr. Ramchandani investigated the efficacy of varenicline, a nicotinic receptor partial agonist, in drinking reduction. SBEI participated as a collaborator for this study. As part of the study, participants underwent an fMRI session in which they played the RID task to investigate the effect of varenicline on the brain reward system activated by alcohol cues. Cues signaling alcohol reward activated the ventral striatum, in the placebo group, but not in the varenicline group (Vatsalya et al., 2015). Medication repurposing of varenicline could be targeted towards reward-drinking individuals seeking help for treatment of alcohol use disorder. c. Reward Incentive Delay with Shock Task. We are currently 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. Light drinkers and non-treatment seeking heavy drinkers are being enrolled in an fMRI study, where they are able to earn points for real alcohol and food rewards at the risk of receiving a small electric shock. This study is ongoing. d. RID Task for Ghrelin Study. A study, conducted in collaboration with Dr. Leggio, uses the RID task 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. e. Dynamic MID Task for NORAA Study. A dynamic version of the MID task is being utilized in a collaboration with Dr. Hibbeln. In this study the effects of Omega-3 in adults with ADHD is being investigated, through the response of reward system circuitry. SBEI has assisted in the design of this study and oversees the imaging components. f. Effort Task. SBEI has also examined the role of alcohol dependence in effort-based valuation. We investigated this phenomenon in a population of treatment seeking alcohol dependent participants and healthy controls. Participants underwent an fMRI scan during which they played a task, which instructed participants to exert effort, in order to earn a monetary reward (Grodin et al., under review). There were three trial types, two where the level of effort was indicated to the subject (low and high), and one experimental condition where there was no indication of the required effort. Behaviorally, ADPs were less motivated during high effort trials and were less willing to exert higher levels of effort when the effort level was undisclosed. During low effort and unknown effort cue presentation, ADPs displayed an increased BOLD signal in clusters containing the dorsal and ventral striatum, regions implicated in effort and motivational processing. 2. fMRI Studies of Decision-Making a. Risk Task. While it has been established that alcohol dependence is associated with an increase in risky decision-making, there has been less focus on the role of past performance in neural activations occurring during and after decision-making. SBEI sought to bridge this gap utilizing a risk-taking fMRI paradigm that gave participants updated feedback on cumulative earnings throughout the task (Gilman et al., 2014). We analyzed the dynamic influence of trial-to-trail changes in net gain and loss, examining the activation during choice and feedback phases when modulated by cumulative earnings. ADPs exhibited heightened striatal activation, when cumulative earnings were included as a covariate, during risky decision-making, compared to healthy controls. b. Ultimatum Task. Recently, we have conducted a study utilizing a modified version of the Ultimatum Game, a paradigm where participants are given an offer as to how to divide $20.00. Participants were given the option to accept or reject each offer. Previous studies have demonstrated that the insula plays a key role in the processing of unfair offers. Our fMRI results indicate higher activation in the HCs in the insular cortex to unfair offers that were later rejected. HCs insula activation may have acted as a mediator between an emotional response versus the risk of rejecting such offers. c. Prediction Error Task. One of the remarkable properties of the human brain is its ability to adapt decision-making based on the outcome of previous decisions. Such optimization occurs when the prediction of receiving a reward is in conflict with the outcome, known as a prediction error. We have implemented a modified version of the prediction error task, where participants must select which of two cues they believe is associated with monetary reward. The two cues switch roles pseudo-randomly, with the winning cue becomes the losing cue, and vice-versa. Preliminary results indicate that alcohol dependent participants increase their activation of the caudate and insula when experiencing a prediction error, in comparison to healthy controls. 3. fMRI and Experimental Treatments We provided imaging support for three experimental treatment studies investigating naltrexone, pexacerfont (CRF receptor antagonist), and aprepitant (neurokinin-1 (NK1) receptor antagonist) as potential treatments for participants with alcohol use disorders. Naltrexone increased the activation in the ventral striatum, which indicates that naltrexone may be beneficial in alcohol dependent participants because of its ability to increase ventral striatal activity, thus reversing the reward deficiency syndrome present in those with alcoholism (Spagnolo et al., 2014). Pexacerfont did not affect the BOLD signal in the anxious treatment seeking population evaluated in this study. However, we did observe predictable activation in the amygdala during the presentation of fearful faces in the placebo group, validating our fMRI measures (Kwako et al. 2015). Aprepitant robustly activated the vmPFC during the presentation of aversive stimuli in a population of treatment seeking ADPs with comorbid PTSD, which indicates that NK1 antagonist therapy may be a useful treatment to enhance extinction-based cue-exposure therapies (Kwako et al. 2015). Repetitive Transcranial Magnetic Resonance (rTMS) Study The Risk Task is being used as an index of rTMS effect in a pilot study of cortical stimulation and the role of the insula in risky decision-making. Our preliminary analysis indicates that risk taking behavior was differentially affected by rTMS, resulting in an increased percentage of safe choices, which was sustained at the 1-hr time-point. These results show that 1Hz rTMS modulates insula activity in healthy controls, inducing behavioral effects similar to those described in patients with insula lesions. Given that insula damage leads to profound decreases in drug craving and relapse, rTMS may represent a non-invasive tool to affect craving driven by the insula in addiction.

1. 动机的功能磁共振成像研究 一个。 MID 和 GLP1R。作为与 Leggio 博士合作的一部分，我们对完成 MID 任务的 ADP 的 fMRI 数据进行了分析。 SBEI 的作用是探索 GLP1R 遗传变异与酒精依赖参与者大脑激活的关联（Suchankova 等，2015）。激素胰高血糖素样肽-1 (GLP-1) 参与奖励处理。当对比 rs6923761 SNP 的基因型时，右侧苍白球的大脑激活存在显着差异。当收到高奖励结果通知时，携带非风险等位基因的 ADP 在右侧苍白球中表现出比携带风险等位基因的 ADP 更低的 BOLD 反应。这一发现表明带有风险等位基因的个体可能有一个功能失调的奖励系统。 b. MID 和伐尼克兰。 SBEI 创建了 MID 任务的修改版本，它使用食物和酒精等自然奖励来代替金钱奖励。该任务称为奖励激励延迟（RID）。 Ramchandani 博士研究了伐尼克兰（一种烟碱受体部分激动剂）在减少饮酒方面的功效。 SBEI 作为合作者参与了这项研究。作为研究的一部分，参与者接受了功能磁共振成像（fMRI）测试，其中他们执行 RID 任务，以研究伐尼克兰对酒精提示激活的大脑奖励系统的影响。在安慰剂组中，发出酒精奖赏信号的信号激活了腹侧纹状体，但在伐尼克兰组中则没有（Vatsalya et al., 2015）。伐尼克兰药物的重新利用可以针对寻求酒精使用障碍治疗帮助的奖励性饮酒个体。 c.通过休克任务奖励激励延迟。我们目前正在进行一项新颖的转化研究，以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。轻度饮酒者和未寻求治疗的重度饮酒者正在参加一项功能磁共振成像研究，他们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。这项研究正在进行中。 d. Ghrelin 研究的 RID 任务。与 Leggio 博士合作进行的一项研究，使用 RID 任务来调查 ghrelin 的作用，ghrelin 是一种参与调节饥饿和奖赏感知的神经肽，在未寻求治疗的重度饮酒者人群中对酒精的渴望和使用中的作用。 e. NORAA 研究的动态 MID 任务。与 Hibbeln 博士合作使用了 MID 任务的动态版本。在这项研究中，通过奖励系统电路的反应，研究了 Omega-3 对患有 ADHD 的成人的影响。 SBEI 协助设计了这项研究并监督成像组件。 f.努力任务。 SBEI 还研究了酒精依赖在基于努力的评估中的作用。我们在寻求酒精依赖的参与者和健康对照的治疗人群中调查了这种现象。参与者在执行一项任务时接受了功能磁共振成像扫描，该任务指示参与者付出努力，以获得金钱奖励（Grodin 等人，正在审查中）。共有三种试验类型，其中两种向受试者指示了努力水平（低和高），另一种实验条件没有指示所需的努力。在行为上，ADP 在高努力试验期间的积极性较低，并且在努力水平未公开时不太愿意付出更高水平的努力。在低努力和未知努力线索呈现期间，ADP 在包含背侧和腹侧纹状体、涉及努力和动机处理的区域的簇中显示出增加的 BOLD 信号。 2. 决策的功能磁共振成像研究 一个。风险任务。虽然已经确定酒精依赖与风险决策的增加有关，但人们很少关注过去的表现在决策期间和决策之后发生的神经激活中的作用。 SBEI 试图利用冒险的功能磁共振成像范式来弥补这一差距，该范式为参与者提供了整个任务中累积收入的最新反馈（Gilman 等，2014）。我们分析了试验过程中净收益和损失变化的动态影响，检查了选择和反馈阶段受累积收益调节时的激活情况。与健康对照组相比，在风险决策过程中，当将累计收入作为协变量时，ADP 表现出更高的纹状体激活。 b.最后通牒任务。最近，我们利用最后通牒游戏的修改版本进行了一项研究，在该范例中，参与者被告知如何分配 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，脑岛在处理不公平报价中发挥着关键作用。我们的功能磁共振成像结果表明，岛叶皮质中的 HC 对后来被拒绝的不公平报价有更高的激活。 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。 c.预测错误任务。人脑的显着特性之一是它能够根据先前决策的结果来调整决策。当收到奖励的预测与结果相冲突时（称为预测误差），就会发生这种优化。我们已经实现了预测误差任务的修改版本，参与者必须选择他们认为与金钱奖励相关的两个线索中的哪一个。两个线索伪随机地转换角色，获胜线索变成失败线索，反之亦然。初步结果表明，与健康对照组相比，酒精依赖参与者在遇到预测错误时尾状核和岛叶的激活会增加。 3. fMRI 和实验治疗 我们为三项实验性治疗研究提供影像学支持，研究纳曲酮、pexacerfont（CRF 受体拮抗剂）和阿瑞匹坦（神经激肽-1 (NK1) 受体拮抗剂）作为酒精使用障碍参与者的潜在治疗方法。纳曲酮增加了腹侧纹状体的激活，这表明纳曲酮可能对酒精依赖的参与者有益，因为它能够增加腹侧纹状体的活动，从而逆转酒精中毒者中存在的奖赏缺乏综合征（Spagnolo et al., 2014）。 Pexacerfont 不会影响本研究评估的寻求治疗的焦虑人群中的 BOLD 信号。然而，我们确实观察到安慰剂组在呈现恐惧面孔时杏仁核的可预测激活，验证了我们的功能磁共振成像测量（Kwako et al. 2015）。在寻求 ADP 治疗并伴有 PTSD 的人群中，阿瑞吡坦在出现厌恶刺激时强烈激活了 vmPFC，这表明 NK1 拮抗剂治疗可能是增强基于消退的线索暴露治疗的有效治疗方法 (Kwako et al. 2015)。 重复经颅磁共振 (rTMS) 研究 在皮层刺激和岛叶在风险决策中的作用的初步研究中，风险任务被用作 rTMS 效果的指标。我们的初步分析表明，冒险行为受到 rTMS 的不同影响，导致安全选择的百分比增加，并且这种情况在 1 小时的时间点持续存在。这些结果表明，1Hz rTMS 调节健康对照者的岛叶活动，诱导与岛叶病变患者相似的行为效应。鉴于岛叶损伤会导致药物渴望和复发的大幅减少，rTMS 可能是一种非侵入性工具，可以影响成瘾过程中岛叶驱动的渴望。