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

项目摘要 可卡因使用障碍（CUD）是少数几种没有有效治疗的物质使用障碍之一。 药物治疗.一个假设的机制，有助于不妥协的CUD是失调， 大脑铁平衡的关键铁稳态是一个重要的生物学机制，但一直被忽视 在成瘾研究中。为了证实以前的报告，我们的研究小组最近证明， 在非寻求治疗的CUD患者中显著升高。然而，虽然脑铁含量升高 与衰老中的认知能力下降和神经退行性疾病的疾病严重程度有关， CUD的神经生物学和临床相关性仍然未知。这个项目的目标是建立影响 脑铁失调的症状。 我们建议调查是否升高脑铁在CUD有助于疾病的严重程度， 通过与不良治疗结果相关的措施： 执行控制和边缘唤醒神经网络以及行为和认知缺陷。要全面完成 这利用了先进的定量MRI方法，对脑铁和神经系统的敏感性和特异性 微观结构，在这方面我们的小组有特别的专长，专注于认知措施一贯发现 在CUD中异常。该项目的总体假设是，通过增加氧化损伤的风险， 细胞死亡，CUD中脑铁的过量积累有助于脑内神经微结构受损 神经网络与这种疾病有关，并与执行控制中的行为和认知缺陷有关 和基于奖励的决策。证明CUD中脑铁升高的不良影响将 建立脑铁失调作为一个有前途的治疗目标，为未来的研究CUD。

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.