Establishing the Neurostructural and Clinical Impact of Brain Iron Dysregulation in Cocaine Use Disorder

项目总结 可卡因使用障碍(Cud)是为数不多的没有有效治疗方法的药物使用障碍之一。 药物疗法。导致CUD不妥协的一个假设机制是监管失调 脑铁稳态的影响。铁稳态是一个关键的生物学机制，但在很大程度上被忽视了 在成瘾研究方面。证实了之前的一份报告，我们的团队最近证明了大脑铁是 在未寻求治疗的CUD患者中显著升高。然而，虽然升高的脑铁有 与衰老中的认知衰退和神经退行性疾病的疾病严重性有关， CUD的神经生物学和临床相关性仍不清楚。这个项目的目标是建立影响 CUD患者的脑铁代谢失调。 我们建议研究慢性阻塞性肺病患者脑内铁含量升高是否与疾病的严重程度有关。 通过与不良治疗结果相关的措施：脑内异常的神经微结构 执行控制和边缘觉醒神经网络以及行为和认知缺陷。我们将完成 这利用了先进的定量MRI方法，这些方法对脑铁和神经具有敏感性和特异性 微观结构，我们小组在这方面有特殊的专业知识，专注于认知测量，一直发现 在CUD中是异常的。这个项目的总体假设是，通过增加氧化损伤的风险和 细胞死亡，脑内铁过量积聚导致脑内神经微结构受损 网络与这种障碍有关，并与执行控制中的行为和认知缺陷有关 以及以奖励为基础的决策。证明脑铁升高对CUD的不利影响 建立脑铁失调作为未来CUD研究的有前景的治疗靶点。

PROJECT SUMMARY Cocaine use disorder (CUD) is among the few substance use disorders without an effective pharmacotherapy. One hypothesized mechanism contributing to the intransigence of CUD is the dysregulation of brain iron homeostasis. Iron homeostasis is a critical biological mechanism that has been largely overlooked in addiction research. Corroborating a previous report, our group recently demonstrated that brain iron is significantly elevated in non-treatment seeking individuals with CUD. However, while elevated brain iron has been associated with cognitive decline in aging and disease severity in neurodegenerative diseases, the neurobiological and clinical relevance in CUD remain unknown. The goal of this project is to establish the impact of brain iron dysregulation in CUD. We propose to investigate whether elevated brain iron in CUD contributes to disease severity as defined by measures that have been associated with poor treatment outcome: aberrant neural microstructure within the executive control and limbic arousal neural networks and behavioral and cognitive deficits. We will accomplish this utilizing advanced, quantitative MRI methods that are sensitive and specific for brain iron and neural microstructure, in which our group has particular expertise, focusing on cognitive measures consistently found as aberrant in CUD. The overall hypothesis of this project is that, by increasing the risk of oxidative damage and cell death, excess buildup of brain iron in CUD contributes to compromised neural microstructure within brain networks implicated in the disorder and are associated with behavioral and cognitive deficits in executive control and reward-based decision making. Demonstrating the adverse impact of elevated brain iron in CUD would establish brain iron dysregulation as a promising therapeutic target for future studies of CUD.