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: 8901123
• 负责人: Liangsuo Ma
• 金额: $ 33.8万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901123
• 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; Health; Impulsivity; Inferior; Intake; Lead; Measures; 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; System; Testing; Thalamic structure; Therapeutic; Ventral Striatum; Work; addiction; base; blood oxygen level dependent; causal model; cognitive function; frontal lobe; improved; non-drug; 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对多巴胺能药物治疗反应的神经元连接。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。 先前的研究表明，纹状体DA和前额叶皮质活动之间存在显着的相关性， 可卡因依赖者（CD）。然而，目前尚不清楚在CD中，前额叶皮质（PFC）是否会因果影响纹状体，反之亦然。这是相关的，因为前额叶-纹状体通路可能参与纹状体DA释放的多巴胺能调节，导致CD中的低DA。CD中的多巴胺能低下状态可能会破坏额叶抑制，导致对强迫性药物摄入的抑制控制较差。此外，CD中的低DA可能通过纹状体对PFC和其他皮质区域之间连接的门控来影响认知功能。有证据表明，DA回路中CD之间预先存在的差异可能是对治疗反应性的差异的基础，并且对于具有预先存在的低多巴胺能状态的CD，DA增强可能是药物治疗的有用靶点。 该项目将使用随机DCM，这是最近的DCM扩展，考虑到神经元和血管反应的隐藏波动，因此特别适合研究疾病或药物的影响。此外，该项目将使用非线性DCM，DCM扩展，可以测量纹状体对皮质-皮质通路的门控效应。本项目的总体目标是：（1）进行基于功能磁共振成像的工作记忆和冲动性DCM研究，以确定与非药物使用对照相比，寻求治疗的CD中PFC和纹状体之间的有效（方向）连接。我们假设DLPFC因果影响腹侧纹状体的CD，这种连接的强度是较低的CD相比，控制。(2)确定背侧纹状体的预处理门控效应是否反映了与慢性强迫性药物使用相关的预处理多巴胺能减退状态，可预测CD患者对多巴胺能药物治疗的治疗反应。我们假设背侧纹状体对前额-顶叶有效连接的预处理门控较低，预测DA增强药物治疗CD（联合认知行为治疗[CBT]）的12周改善较大，但安慰剂治疗（联合CBT）则不然。 建立PFC和纹状体之间的定向关系和纹状体门控在可卡因治疗反应中的作用将显着提高我们对CD中多巴胺能药理学机制的理解，并可能最终导致有用的可卡因依赖及其治疗的生物标志物。