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.

项目总结 药物成瘾的特征是普遍存在的神经认知损害，这种损害会加剧和维持 生病了。这些损害是在基本的一阶领域观察到的，如工作记忆，持续的 注意力和决策，但也在二阶意识到一阶的严重性 缺陷(即，元认知：“思考思考”)。重要的是，(二阶)元认知缺陷可能 从概念和经验上从基本(一阶)赤字中解脱出来，暗示 至少部分不同的大脑回路和分子基础，也许是对 对药物使用的预测。在R21的这一应用中，我们首次探索了 药物(阿片)成瘾中的元认知，并将该回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，这也与关键的成瘾症状有关， 例如取款)。阿片使用障碍(OUD)患者(特别是海洛因使用者； 美沙酮维持)和匹配的健康对照组(HC)将完成功能磁共振 成像(FMRI)元认知任务，以前在HC中验证，但在这里首次扩展到OUD。 元认知障碍的行为证据已经开始出现，但这将是第一次 对底层电路的检查。在功能磁共振成像任务中，参与者报告他们对自己的 正在进行的任务精确度与元认知之间存在较高的正相关关系 信心和更好的表现。功能磁共振成像分析检查了逐个试验之间的相关性 信心等级和大脑激活，参数信号预计出现在外侧前额叶 皮质(PFC)和前扣带回皮质(ACC)。在整个任务中使用眼球跟踪来收集 有关蓝斑(LC)去甲肾上腺素参与的公认标志--瞳孔扩张的信息。小学生 在LC中，扩张作为去甲肾上腺素功能的标志被神经黑素敏感的MRI补充， 儿茶酚胺终生累积分解的创新标记，包括去甲肾上腺素，它 慢性药物成瘾时可能出现异常信号及其对去甲肾上腺素能的影响 系统。具体目标包括测试OUD和HC在元认知行为上的群体差异 和神经功能，并将元认知相关异常的程度与 去甲肾上腺素的功能和药物使用的严重性。如果观察到预期的关系，我们的结果将 揭示了一种新的成瘾神经认知缺陷，这种缺陷有可能使药物使用永久化。正性 研究结果还将提示这种损伤的一种新的神经化学机制，这可能是符合 通过去甲肾上腺素治疗进行干预。因此，我们的建议是必要的第一步，符合 R21机制，这将为这一领域奠定基础，并为更大规模的调查提供动力。