Functional Magnetic Resonance Imaging Of Emotion As Related To Alcoholism

与酗酒相关的情绪功能磁共振成像

• 批准号: 8941372
• 负责人: Markus Heilig
• 金额: $ 256.24万
• 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/8941372
• 关键词: Acute; Adult; Affect; Affective; Agonist; Alcohol dependence; Alcoholic beverage heavy drinker; Alcoholism; Alcohols; Amino Acids; Animal Model; Arousal; Attention deficit hyperactivity disorder; Attenuated; Auditory; Biochemistry; Biological Markers; Biological Neural Networks; Biophysics; Brain; Brain region; Categories; Clinical; Clinical Treatment; Collaborations; Comparative Study; Corpus striatum structure; Cues; Data; Data Analyses; Decision Making; Disease; Dopamine; Dose; Double-Blind Method; Eating; Emotional; Emotions; Endocrinology; Ethanol; Evaluation; Experimental Designs; Extinction (Psychology); Fright; Functional Magnetic Resonance Imaging; Guided imagery; Human; Human Genetics; Hypothalamic structure; Image; Image Analysis; Impulsivity; Incentives; Infusion procedures; Intramural Research Program; Investigation; Laboratories; Ligands; Lipopolysaccharides; MRI Scans; Magnetic Resonance Imaging; Manuscripts; Measures; Mediating; Medicine; Membrane; Memory; Methods; Modeling; Motivation; Naltrexone; Narcotic Antagonists; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Neurosciences; Notification; Nutritional; Omega-3 Fatty Acids; Oxytocin; Participant; Pathway interactions; Patients; Pattern; Peptides; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacological Treatment; Pioglitazone; Placebos; Post-Traumatic Stress Disorders; Prefrontal Cortex; Property; Prosencephalon; Psychiatry; Psychopharmacology; Publications; Punishment; Randomized; Reporting; Research Design; Rest; Rewards; Risk; Role; Saline; Severities; Signal Transduction; Stimulus; Structure of nucleus infundibularis hypothalami; Study Subject; Substance P; Substance abuse problem; Symptoms; TACR1 gene; Task Performances; Time; Time Series Analysis; Treatment Efficacy; Variant; Ventral Striatum; Work; alcohol craving; alcohol cue; alcohol effect; alcohol relapse; alcohol response; alcohol reward; alcohol use disorder; approach avoidance behavior; aprepitant; base; biological adaptation to stress; blood oxygen level dependent; craving; design; dopamine system; drug craving; endogenous opioids; genetic association; ghrelin; glucagon-like peptide; growth hormone secretagogue receptor; increased appetite; mathematical methods; method development; motivational processes; mouse model; neural circuit; neuroimaging; novel; positive emotional state; preclinical study; problem drinker; receptor; relating to nervous system; response; sobriety; social; varenicline; visual stimulus

Resting State and Functional Connectivity: Previous studies have shown diverse effects of alcoholism on resting state MRI (rsMRI) connectivity. Long-term alcoholics who were currently in a period of sobriety showed decreased synchrony of limbic reward regions. The results demonstrated abnormal functional connectivity both within and between-network in AD, further supporting the concept that AD is a disorder affecting neural networks. The impaired connectivity in the resting state networks was associated with increased impulsivity in AD. Our findings suggest that the altered resting-state functional connectivity patterns can differentiate AD subjects from HC, and may become an important biomarker for alcohol dependence severity and treatment efficacy (Zhu et al., manuscript prepared for submission). fMRI analysis method development: We developed a linear time-invariant model based on statistical time series analysis in the Fourier domain for single subjects and applied this method to functional MRI (fMRI) blood-oxygen level-dependent (BOLD) multivariate data. This is especially important for experimental designs involving multiple states (either stimulus or drug induced) that may alter the form of the response function (Rio et al., Comput Math Methods Med. 2013; 2013) Medication Studies: a) Naltrexone Our section has designed fMRI tasks and analyzed the imaging data of Effect of Naltrexone on Craving and Ethanol-Induced Brain Activity, by the CATE (Dr. George) section. Positively reinforcing properties of alcohol is in part mediated by activation of the ventral striatum (VS). Alcohol-induced release of endogenous opioids is thought to contribute to this response. Preclinical studies show that the opioid antagonist naltrexone (NTX) can block this cascade, but its ability to do so in treatment seeking alcoholics has not been examined. Participants received a saline infusion followed by alcohol, and also viewed affective stimuli in an MR scanner. Irrespective of medication treatment condition, and in contrast to prior findings in social drinkers, alcohol infusion did not activate the VS in the alcohol dependent patients. Unexpectedly, and across all other conditions, VS activation was greater in NTX treated patients than in the PLC group. NTX treated patients also reported increased craving in response to alcohol cue exposure compared to PLC subjects (Spagnolo et al., accepted publication, ACER 2014). b) PTSD: Our section has designed fMRI imaging tasks and analyzed the imaging data of The Effect of NK1R Antagonism on Alcohol Craving and PTSD Symptoms in Alcohol Dependent Patients with PTSD, by the CATE (Dr. George) Section. Post-traumatic stress disorder (PTSD) and alcoholism are frequently co-morbid. This study was designed to determine the neural effects of neurokinin 1 (NK1) antagonist aprepitant on alcohol-dependent subjects with PTSD. Fifty-three patients with PTSD and alcoholism were admitted for 4 weeks to this experimental medicine study. In this randomized and double-blind study subjects fMRI responses to stimuli with positive or negative emotional valence were analyzed. In this study we found treatment group robustly potentiated ventromedial prefrontal cortex (vmPFC) responses to aversive visual stimuli. This region of brain is critical for extinction of fear memories and in alcohol craving and relapse risk, our finding suggests that NK1 antagonism, rather than acutely attenuating stress responses, might be a useful pharmacological treatment to enhance the effect of extinction-based cue-exposure therapies (Kwako, et al., accepted publication AJP 2014). c) Varenicline: Our section has designed fMRI imaging tasks and analyzed the imaging data of the study conducted by Section on Human Psychopharmacology (Dr. Ramchandani). In this double-blind randomized study subjects were randomized to receive Varenicline or placebo for 3 weeks. Participants underwent an fMRI scan while performing a variation of the MID task designed to evaluate the incentive salience of alcohol cues. A direct contrast of treatment groups showed significantly lower activation in Varenicline compared to placebo group. These results indicate significant activation of striatal regions to alcohol cues and notification of alcohol reward in the placebo but not in the Varenicline group. This suggests that Varenicline may exert its effects by modulating the neural substrates underlying motivation for and incentive salience of alcohol reward in heavy drinkers (Vatsalya, et al., submitted JAMA Psychiatry). d) BMS: Our section has designed fMRI imaging tasks and analyzed the imaging data of the study designed and conducted by the Section on Clinical and Treatment Evaluation. Patients went under a randomized double-blind pexacerfont. After reaching steady state, subjects were assessed for fMRI responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. Based on conventional analyses of fMRI data, Pexacerfont treatment had no effect (Manuscript submitted, NPP). e) Pioglitozone: Our section is providing design, implementation and analyses of fMRI component of a study aimed to evaluate the role of proinflammatory signalling in alcohol craving. The peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone, which modulates glial activity, will be used as an experimental treatment. Guided imagery auditory scripts will be used as an established set of stimuli to induce craving. Low dose lipopolysaccharide (LPS) administration which activates proinflammatory signaling will be used as a novel challenge, and evaluated for its ability to provoke alcohol craving. If LPS in fact induces alcohol craving, the present design will allow evaluation of whether pioglitazone can inhibit this response. f) GSK: Our section is providing design, implementation and analyses of fMRI component of a study aimed to evaluate pexacerfont, an orally available, brain penetrant selective CRH1 antagonist for its ability to modulate emotional and motivational processes in anxious, recently detoxified alcohol dependent pa Other Collaborations In addition to LCTS, Our section has provided fMRI expertise to other sections and laboratories within NIAAA Intramural program. Among those: We provided fMRI support material to The Section on Clinical Psychoneuro-endocrinology and Neuropsychopharmacology ((CPN) Dr. Lorenzo Legio). Through data analysis from our Monetary Incentive Delay (MID) studies we provided support to a study on the potential of glucagon-like peptide-1 receptor as a treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence (submitted for publication AJP). Our section has designed and assisted the CPN section in conducting a study involving Ghrelin, a 28-amino acid peptide acting as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus (ARC), a region that controls the intake of food and other substances, including alcohol. The imaging component of this study involves investigating how the infusion of Ghrelin and acute ethanol impacts tasks performance and resting state fMRI. Our section has also provided support in designing the fMRI component of a B2B study (Dr. Mary Lee) by CPN section to study the effects of oxytocin in alcohol dependence. Our Section has also assisted the Section on Nutritional Neurosciences (Dr. Joseph Hibblen), Laboratory of Membrane Biochemistry and Biophysics to design, implement, and conduct the Neuroimaging Omega-3 and Reward in Adults with ADHD trial.

静息状态和功能连接： 先前的研究表明，酗酒对静息态 MRI (rsMRI) 连接性有多种影响。目前处于清醒期的长期酗酒者表现出边缘奖励区域的同步性下降。结果表明 AD 网络内部和网络之间的功能连接异常，进一步支持 AD 是一种影响神经网络的疾病的概念。静息状态网络的连通性受损与 AD 的冲动性增加有关。我们的研究结果表明，改变的静息态功能连接模式可以区分 AD 受试者和 HC，并且可能成为酒精依赖严重程度和治疗效果的重要生物标志物（Zhu 等人，准备提交的手稿）。 fMRI分析方法开发： 我们针对单个受试者开发了一种基于傅立叶域统计时间序列分析的线性时不变模型，并将该方法应用于功能性 MRI (fMRI) 血氧水平依赖 (BOLD) 多变量数据。这对于涉及可能改变响应函数形式的多种状态（刺激或药物诱导）的实验设计尤其重要（Rio 等人，Comput MathMethods Med. 2013；2013） 药物研究： a) 纳曲酮 我们部门设计了功能磁共振成像任务，并分析了 CATE（乔治博士）部门的“纳曲酮对渴望和乙醇诱导的大脑活动的影响”的成像数据。酒精的正增强特性部分是由腹侧纹状体（VS）的激活介导的。酒精诱导的内源性阿片类药物的释放被认为有助于这种反应。临床前研究表明，阿片类拮抗剂纳曲酮（NTX）可以阻断这种级联反应，但其在治疗酗酒者中的能力尚未得到检验。 参与者先注射生理盐水，然后注射酒精，并在磁共振扫描仪中观察情感刺激。无论药物治疗情况如何，与之前在社交饮酒者中的研究结果相反，酒精输注并没有激活酒精依赖患者的 VS。出乎意料的是，在所有其他条件下，NTX 治疗组患者的 VS 激活程度高于 PLC 组。与 PLC 受试者相比，NTX 治疗的患者还报告了对酒精提示暴露的渴望增加（Spagnolo 等人，已接受出版物，ACER 2014）。 b) 创伤后应激障碍： 我们部门设计了功能磁共振成像任务，并分析了 CATE（乔治博士）部门的《NK1R 拮抗剂对患有 PTSD 的酒精依赖患者的酒精渴望和 PTSD 症状的影响》的成像数据。创伤后应激障碍（PTSD）和酗酒通常是共病的。本研究旨在确定神经激肽 1 (NK1) 拮抗剂阿瑞吡坦对患有 PTSD 的酒精依赖受试者的神经影响。 53 名患有 PTSD 和酗酒的患者被纳入这项实验性医学研究，为期 4 周。在这项随机双盲研究中，分析了受试者对积极或消极情绪效价刺激的功能磁共振成像反应。在这项研究中，我们发现治疗组的腹内侧前额皮质（vmPFC）对厌恶性视觉刺激的反应明显增强。大脑的这个区域对于恐惧记忆的消除、酒精渴望和复发风险至关重要，我们的发现表明 NK1 拮抗作用，而不是急剧减弱应激反应，可能是一种有用的药物治疗，可以增强基于消除的线索暴露疗法的效果（Kwako 等人，接受出版物 AJP 2014）。 c) 伐尼克兰： 我们部门设计了功能磁共振成像任务，并分析了人类精神药理学部门（Ramchandani 博士）进行的研究的成像数据。在这项双盲随机研究中，受试者随机接受 Varenicline 或安慰剂治疗 3 周。参与者在执行 MID 任务的同时接受功能磁共振成像扫描，该任务旨在评估酒精线索的激励显着性。治疗组的直接对比显示，与安慰剂组相比，Varenicline 的激活显着降低。这些结果表明，在安慰剂组中，纹状体区域对酒精提示和酒精奖励通知有显着激活，但在瓦尼克兰组中则不然。这表明伐尼克兰可能通过调节重度饮酒者酒精奖励的潜在动机和刺激显着性的神经底物来发挥其作用（Vatsalya 等人，提交给 JAMA Psychiatry）。 d) 电池管理系统： 我们部门设计了fMRI成像任务，并分析了临床和治疗评估部门设计和进行的研究的成像数据。患者接受随机双盲 pexacerfont 治疗。达到稳定状态后，评估受试者对酒精相关刺激或具有积极或消极情绪效价的刺激的功能磁共振成像反应。根据功能磁共振成像数据的常规分析，Pexacerfont 治疗没有效果（手稿已提交，NPP）。 e) 吡格列酮： 我们的部分正在提供一项研究的功能磁共振成像部分的设计、实施和分析，旨在评估促炎症信号传导在酒精渴望中的作用。调节神经胶质细胞活性的过氧化物酶体增殖物激活受体 γ (PPARγ) 激动剂吡格列酮将被用作实验性治疗。引导想象听觉脚本将被用作一组既定的刺激来诱发渴望。激活促炎信号传导的低剂量脂多糖（LPS）将被用作新的挑战，并评估其激发酒精渴望的能力。如果 LPS 实际上会引起对酒精的渴望，则本设计将允许评估吡格列酮是否可以抑制这种反应。 f) 葛兰素史克： 我们的部门正在提供一项研究的功能磁共振成像部分的设计、实施和分析，该研究旨在评估 pexacerfont，一种口服的、脑渗透性选择性 CRH1 拮抗剂，其调节焦虑、最近戒毒的酒精依赖者的情绪和动机过程的能力 其他合作 除了 LCTS 之外，我们部门还向 NIAAA 校内计划内的其他部门和实验室提供 fMRI 专业知识。其中： 我们向临床心理神经内分泌学和神经精神药理学科（(CPN) Lorenzo Legio 博士）提供了功能磁共振成像支持材料。通过货币激励延迟 (MID) 研究的数据分析，我们为一项关于胰高血糖素样肽 1 受体作为酒精使用障碍治疗靶点的潜力的研究提供了支持：来自人类遗传关联研究和酒精依赖小鼠模型的证据（已提交 AJP 出版）。 我们部门设计并协助 CPN 部门进行了一项涉及 Ghrelin 的研究，Ghrelin 是一种 28 个氨基酸的肽，充当生长激素促分泌素受体 (GHS-R) 的内源配体。胃饥饿素通过作用于下丘脑弓状核 (ARC) 来刺激食欲，该区域控制食物和其他物质（包括酒精）的摄入。本研究的成像部分涉及研究 Ghrelin 和急性乙醇的输注如何影响任务表现和静息态功能磁共振成像。 我们部门还为 CPN 部门设计 B2B 研究（Mary Lee 博士）的 fMRI 部分提供支持，以研究催产素对酒精依赖的影响。 我们科还协助营养神经科学科（Joseph Hibblen 博士）、膜生物化学和生物物理学实验室设计、实施和进行 ADHD 成人神经影像 Omega-3 和奖励试验。