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

点击翻译按钮获取中文摘要

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.