Striatal Effective Connectivity to Predict Treatment Response in Cocaine Misuse

纹状体有效连接可预测可卡因滥用的治疗反应

• 批准号: 8458266
• 负责人: Liangsuo Ma
• 金额: $ 34.31万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458266
• 关键词: Accounting; Activation Analysis; Affect; Biological Markers; Blood Vessels; Brain; Brain region; Chronic; Cocaine; Cocaine Dependence; Cognitive Therapy; Corpus striatum structure; Coupling; Development; Disease; Dopamine; Dorsal; Drug Addiction; Drug usage; Functional Magnetic Resonance Imaging; Glutamates; Impulsivity; Inferior; Intake; Lead; Measures; Modeling; Neurons; Nonlinear Dynamics; Outcome; Parietal; Parietal Lobe; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Placebos; Prefrontal Cortex; Public Health; Regulation; Role; Sampling; Severities; Short-Term Memory; Signal Transduction; Study models; System; Testing; Thalamic structure; Therapeutic; Ventral Striatum; Work; addiction; base; blood oxygen level dependent; cognitive function; frontal lobe; improved; non-drug; public health relevance; response; theories; transmission process; treatment response

DESCRIPTION (provided by applicant): This project will use dynamic causal modeling (DCM) to investigate neuronal connectivity underlying treatment response to dopaminergic medications in cocaine dependence. Since reduced dopamine (DA) function is likely to be involved in cocaine dependence, improved understanding of DA neuronal systems in cocaine dependence would facilitate the development of new medications to treat cocaine dependence. Previous studies have shown significant correlations between striatal DA and prefrontal cortical activity in cocaine dependent subjects (CDs). However, it is unclear whether the prefrontal cortex (PFC) causally affects the striatum or vice versa in CDs. This is relevant because the prefrontal-striata pathway may be involved in glutamatergic regulation of striatal DA release leading to low DA in CDs. The hypodopaminergic state in CDs may disrupt frontal inhibition, resulting in poor inhibitory control over compulsive drug intake. In addition, low DA in CDs may affect cognitive functions via striatum's gating of connections between PFC and other cortical regions. There is evidence that preexisting differences between CDs in DA circuits may underlie variability in responsiveness to treatments, and that for CDs who have a preexisting hypodopaminergic state, DA enhancement may be a useful target for pharmacotherapy. This project will use stochastic DCM, which is a recent DCM extension that takes into account hidden fluctuations in neuronal and vascular responses, and thus is especially suited for investigating effects of disease or drugs. In addition, this project will use nonlinear DCM, a DCM extension that can measure gating effects by striatum on cortico-cortical pathways. The overall aims of this project are: (1) To conduct functional magnetic resonance imaging-based DCM studies of working memory and impulsivity in order to determine the effective (directional) connectivity between PFC and striatum in treatment-seeking CDs compared to non-drug using controls. We hypothesize that DLPFC causally affects ventral striatum in CDs, and that the strength of this connection is lower in CDs compared to controls. (2) To determine whether the pretreatment gating effect by the dorsal striatum, as a reflection of pretreatment hypodopaminergic state associated with chronic compulsive drug use, predicts the treatment response to dopaminergic pharmacotherapy in CDs. We hypothesize that lower pretreatment gating by the dorsal striatum on prefrontal-parietal effective connectivity predicts greater 12-week improvement from treatment of CDs with DA enhancing medications (combined with cognitive behavioral therapy [CBT]), but not from treatment with placebo (combined with CBT). Establishing the directional relationship between the PFC and striatum and the role of striatal gating in cocaine treatment response will significantly improve our understanding of dopaminergic pharmacotherapeutic mechanisms in CDs and may ultimately lead to useful biomarkers for cocaine dependence and its treatment.

描述（由申请人提供）：本项目将使用动态因果模型（DCM）来研究可卡因依赖患者多巴胺能药物治疗反应背后的神经元连接。由于多巴胺（DA）功能的降低可能与可卡因依赖有关，因此对可卡因依赖中的DA神经元系统的进一步了解将有助于开发治疗可卡因依赖的新药物。先前的研究显示纹状体DA和前额叶皮层活动之间有显著的相关性