Striatal Effective Connectivity to Predict Treatment Response in Cocaine Misuse

描述(由申请人提供)：这个项目将使用动态因果模型(DCM)来研究可卡因依赖中对多巴胺能药物治疗反应的神经元连接。由于多巴胺(DA)功能降低可能与可卡因依赖有关，对可卡因依赖中DA神经元系统的深入了解将有助于开发治疗可卡因依赖的新药。以往的研究表明，纹状体DA和前额叶皮质活动之间存在显著的相关性。 可卡因依赖受试者(CD)。然而，目前尚不清楚在CDS中，前额叶皮质(PFC)是否因果地影响纹状体，或者反之亦然。这是相关的，因为前额-纹状体通路可能参与了纹状体DA释放的谷氨酸能调节，从而导致CDS中DA的降低。CDS的低多巴胺能状态可能破坏额叶抑制，导致对强迫性药物摄入的抑制控制较差。此外，CDS中低多巴胺可能通过纹状体门控PFC和其他皮质区域之间的联系而影响认知功能。有证据表明，DA回路中预先存在的CDs之间的差异可能是治疗反应差异的基础，对于先前存在低多巴胺状态的CDs，DA增强可能是药物治疗的有用靶点。这个项目将使用随机DCM，这是最近的DCM扩展，它考虑了神经元和血管反应的隐藏波动，因此特别适合于研究疾病或药物的影响。此外，该项目将使用非线性DCM，这是一种DCM扩展，可以测量纹状体对皮质通路的门控效应。本项目的总体目标是：(1)对工作记忆和冲动性进行基于功能磁共振成像的DCM研究，以确定与非药物使用对照相比，在寻求治疗的CD中PFC和纹状体之间的有效(方向性)连接。我们假设DLPFC对CDS患者的腹侧纹状体有因果影响，与对照组相比，CDS患者这种联系的强度较低。(2)确定背侧纹状体的预处理门控效应是否能预测CDS患者对多巴胺能药物治疗的反应。我们假设，降低纹状体对前额顶叶有效连通性的预处理门控预示着使用DA增强药物(结合认知行为疗法[CBT])治疗CDS 12周后的改善更大，而不是使用安慰剂(结合CBT)治疗。建立PFC和纹状体之间的定向关系以及纹状体门控在可卡因治疗反应中的作用将极大地提高我们对CDS中多巴胺能药物治疗机制的理解，并最终可能导致有用的可卡因依赖及其治疗的生物标志物。

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.