Neural and neurochemical correlates of metacognition impairment in opioid addiction

项目摘要 药物成瘾的特征是普遍的神经认知障碍，这些障碍加剧并维持了 病这些损伤在基本的一阶域中观察到，例如工作记忆，持续的 注意力，和决策，而且在第二阶意识的严重性，第一阶 缺陷（即，元认知：“思考思考”。重要的是，（二阶）元认知缺陷可以 从概念上和经验上脱离基本（一阶）赤字，表明参与 至少部分不同的大脑回路和分子基础，也许是一个互补的贡献， 药物使用的预测。在这个R21应用程序中，我们第一次探测了 药物（阿片类药物）成瘾中的元认知，并将这种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（其也明显涉及关键的成瘾治疗学， 如退出）。阿片类药物使用障碍（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（HC）将完成功能性磁共振成像 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。 OUD患者元认知障碍的行为证据已经开始出现，但这将是第一个 检查底层电路。在fMRI任务中，参与者报告他们对自己的信心。 进行中的任务准确性，与元认知操作性之间的正相关性较高 信心和更好的表现。功能磁共振成像分析检查了试验与试验之间的相关性， 置信度和大脑激活，参数信号预计将出现在外侧前额叶 前扣带皮层（ACC）。在整个任务中使用眼动跟踪来收集 瞳孔扩张的信息，蓝斑（LC）-去甲肾上腺素参与的公认标志物。瞳孔 LC中神经黑素敏感MRI补充了扩张作为去甲肾上腺素能功能标志物， 创新的标志物，包括去甲肾上腺素在内的儿茶酚胺的终生累积分解， 由于慢性药物暴露及其对去甲肾上腺素能神经元的影响， 系统具体目标包括测试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 去甲肾上腺素能功能和药物使用严重程度。如果预期的关系得到观察，我们的结果将 揭示了成瘾中一种新的神经认知缺陷，这种缺陷有可能使药物使用永久化。积极 研究结果还将提出一种新的神经化学机制的损害，这可能是服从 通过去甲肾上腺素能疗法进行干预。因此，我们的建议是必要的第一步，符合《联合国宪章》， R21机制，这将在这一领域奠定基础，并为更大规模的调查提供动力。

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.