Neural and neurochemical correlates of metacognition impairment in opioid addiction

阿片类药物成瘾元认知障碍的神经和神经化学相关性

• 批准号: 9890580
• 负责人: Scott J Moeller
• 金额: $ 23.93万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890580
• 关键词: Abstinence; Addictive Behavior; Anterior; Awareness; Behavior; Behavioral; Biological; Biological Assay; Brain; Catecholamines; Choice Behavior; Chronic; Clinical; Cognition; Data; Data Sources; Decision Making; Diagnostic; Drug Addiction; Drug Exposure; Drug usage; Exploratory/Developmental Grant; Foundations; Functional Magnetic Resonance Imaging; Heroin Users; Impairment; Individual; Influenza; Intervention; Investigation; Judgment; Laboratories; Lateral; Lead; Light; Link; Magnetic Resonance Imaging; Measures; Methadone; Methodology; Methods; Molecular; Monitor; Mydriasis; Neurobiology; Neurocognitive Deficit; Neurophysiology - biologic function; Neuropsychology; Norepinephrine; Opiate Addiction; Opioid; Outcome; Participant; Performance; Pharmaceutical Preparations; Pharmacology; Population; Prefrontal Cortex; Recurrence; Reporting; Research; Self Perception; Severities; Short-Term Memory; Signal Transduction; Structure; Symptoms; System; Testing; Therapeutic; Thinking; Time; United States; Withdrawal; Withdrawal Symptom; addiction; base; chronic pain patient; cingulate cortex; combat; innovation; interest; locus ceruleus structure; metacognition; multimodality; neural circuit; neurochemistry; neuroimaging; neuromechanism; neuromelanin; new therapeutic target; noradrenergic; novel; novel therapeutics; opioid epidemic; opioid use; opioid use disorder; relating to nervous system; sustained attention; symptomatology; visual tracking

PROJECT SUMMARY Drug addiction is characterized by pervasive neurocognitive impairments that exacerbate and maintain the illness. These impairments are observed in basic, first-order domains, such as working memory, sustained attention, and decision-making, but also in second-order awareness regarding the severity of the first-order deficits (i.e., metacognition: “thinking about thinking”). Importantly, (second-order) metacognition deficits can be conceptually and empirically disentangled from the basic (first-order) deficits, suggesting the involvement of at least partly distinct brain circuits and molecular underpinnings, and perhaps a complementary contribution to the prediction of drug use. In this R21 application, we probe for the first time the neural circuitry of metacognition in drug (opioid) addiction, and link deficits in this circuitry to a novel neurochemical mechanism: functioning of the noradrenergic system (which notably is also implicated in key addiction symptomatology, such as withdrawal). Individuals with opioid use disorder (OUD) (specifically who are users of heroin; methadone-maintained) and matched healthy controls (HC) will complete a functional magnetic resonance imaging (fMRI) metacognition task, previously validated in HC, but here extended for the first time to OUD. Behavioral evidence of metacognitive impairment in OUD has started to emerge, but this will be the first examination of the underlying circuitry. During the fMRI task, participants report their confidence in their ongoing task accuracy, with metacognition then operationalized as the positive correlation between higher confidence and better performance. The fMRI analyses examine the trial-by-trial correlation between confidence ratings and brain activation, with parametric signals expected to emerge in the lateral prefrontal cortex (PFC) and anterior cingulate cortex (ACC). Eye-tracking is used throughout the task to collect information on pupil dilation, a recognized marker of locus coeruleus (LC)- norepinephrine engagement. Pupil dilation as a marker of noradrenergic function is supplemented by neuromelanin-sensitive MRI in the LC, an innovative marker of the lifetime cumulative breakdown of catecholamines including norepinephrine, which may show an abnormal signal in addiction due to chronic drug exposure and its effects on the noradrenergic system. Specific Aims include testing for group differences between OUD and HC in metacognition behavior and neural function, and relating the extent of the metacognition-related abnormalities to measures of noradrenergic functioning and drug use severity. If the anticipated relationships are observed, our results will shed light on a novel neurocognitive deficit in addiction that has the potential to perpetuate drug use. Positive results will also suggest a novel neurochemical mechanism of the impairment, which may be amenable to intervention via noradrenergic therapeutics. Thus, our proposal is a necessary first step, consistent with the R21 mechanism, that will establish a foundation in this field and provide the impetus for larger investigations.

项目概要 药物成瘾的特点是普遍的神经认知障碍，使药物成瘾恶化并维持 这些损伤是在基本的、一级的领域中观察到的，例如工作记忆、持续性。 注意力和决策，而且还对一阶问题的严重性进行二阶意识 重要的是，（二阶）元认知缺陷可以。 在概念上和经验上与基本（一阶）赤字脱节，表明参与 至少部分不同的大脑回路和分子基础，也许是对 在这个 R21 应用中，我们首次探测了药物使用的神经回路。 药物（阿片类药物）成瘾中的元认知，并将该电路中的缺陷与一种新的神经化学机制联系起来： 去甲肾上腺素能系统的功能（值得注意的是，它也与关键的成瘾症状有关， 患有阿片类药物使用障碍 (OUD) 的人（特别是海洛因使用者； 美沙酮维持）和匹配的健康对照（HC）将完成功能性磁共振 成像（fMRI）元认知任务，之前在 HC 中得到验证，但在这里首次扩展到 OUD。 OUD 元认知障碍的行为证据已经开始出现，但这将是第一个 在功能磁共振成像任务期间，参与者报告了他们对自己的信心。 持续任务​​的准确性，然后将元认知操作为较高水平之间的正相关性 信心和更好的表现之间的逐个试验的相关性进行了功能磁共振成像分析。 信心评级和大脑激活，参数信号预计会出现在外侧前额叶 整个任务中使用眼动追踪皮层（PFC）和前扣带皮层（ACC）来收集数据。 瞳孔扩张的信息，这是蓝斑（LC）-去甲肾上腺素瞳孔参与的公认标志。 扩张作为去甲肾上腺素能功能的标志物，由 LC 中的神经黑色素敏感 MRI 进行补充， 包括去甲肾上腺素在内的儿茶酚胺终生累积分解的创新标记物， 由于慢性药物暴露及其对去甲肾上腺素能的影响，可能会显示出成瘾的异常信号 具体目标包括测试 OUD 和 HC 在元认知行为方面的群体差异。 和神经功能，并将元认知相关异常的程度与以下措施联系起来： 如果观察到预期的关系，我们的结果将是去甲肾上腺素能功能和药物使用严重程度。 揭示了一种新的成瘾神经认知缺陷，有可能使药物使用持续下去。 结果还将表明一种新的损伤神经化学机制，这可能适合于 因此，我们的建议是必要的第一步，与之前的研究一致。 R21机制，将为该领域奠定基础，并为更大规模的调查提供动力。