Attentional Bias Modification: Efficacy and Mechanisms of Action in Cocaine Addic

描述（由申请人提供）：可卡因滥用和依赖是一种慢性复发性疾病，几乎没有有效的治疗方法。长时间接触毒品后，额叶和皮层下神经回路的变化可能会在戒烟后持续数年，并可能损害成瘾者在接触毒品相关线索时抑制药物寻求的能力。注意偏向修正（ABM）训练据称可以降低对显著药物刺激的注意反应，并已被证明在治疗酒精依赖方面有效;然而，ABM治疗可卡因成瘾个体的疗效还有待于经验确定。以往的研究表明，慢性可卡因使用者也表现出减少的神经元反应，在抑制控制除了增强神经元反应的显着药物线索。在我们的R 03-ISTART资助期间获得的初步神经成像数据支持这两条研究路线，因为可卡因滥用和依赖（CCA）的个体在对现实可卡因线索的反应中表现出增加的激活，而在抑制控制期间则严重缺乏激活。尽管存在这两种神经元异常的广泛证据，但迄今为止，我们还没有发现直接比较这两种度量的差异有效性的研究（即，增强的线索反应性和降低的抑制控制）来预测复发。此外，我们的初步数据提供了证据，增加内在的神经元活动（功能连接; fcMRI）内的额叶皮层下电路在CCA相对于控制。因此，本申请有两个主要目的，既具有临床意义，又具有高度创新性。首先，我们将研究ABM治疗可卡因成瘾的疗效和作用机制（目的1）。其次，我们将确定三种神经元异常中的哪一种或多种异常（即，增强的线索反应性或降低的抑制控制或增加的fcMRI）更能预测复发和药物利用（探索性目的1）。为了实现这两个目标，40名寻求治疗的CCA将以盲态方式随机分配到两组之一：5次ABM治疗或5次类似的分类对照任务。所有参与者将完成一个广泛的临床和功能磁共振成像电池治疗前和治疗后，旨在测量激活可卡因线索处理，抑制控制和功能连接。我们预测ABM将被证明可以有效减少复发，并且它将在减少与成瘾有关的额叶（眶额皮质和前扣带回）和皮质下（腹侧纹状体）区域的fcMRI和线索反应性方面发挥最大作用。我们还预测，在基线时额叶皮层下回路fcMRI增加的个体更容易复发，这表明重复暴露于可卡因刺激可能导致独立于药物刺激的潜在回路变化。这项研究的目的具有临床意义，因为它们可能为CCA提供新的治疗方法，或者至少检查fcMRI增强、线索反应性增强或抑制控制降低是否更能预测复发。 公共卫生相关性：慢性可卡因滥用和依赖与个人、其支持网络和整个社会的重大医疗、神经、社会和人际并发症有关。对可卡因滥用和依赖只有少数有效的治疗方法，开发更有效的治疗方法至关重要。成瘾者往往对与药物使用相关的线索更加敏感，并且抑制使用药物冲动的能力下降，这两者都可以使用行为和神经成像技术进行测量，例如功能性磁共振成像（fMRI）。注意力偏差修正（ABM）疗法训练个体将注意力从与药物使用相关的线索上转移开，并已被证明对酒精成瘾有效。我们将研究ABM治疗可卡因成瘾的疗效，并使用功能磁共振成像来识别与治疗效果相关的大脑变化。我们还将从我们收集的指标中确定最能预测复发的大脑变化。所有这些目标将提供一个更好的理解成瘾行为的神经生物学原因，其慢性复发的性质，并将直接有助于找到有效的治疗方法。

DESCRIPTION (provided by applicant): Cocaine abuse and dependence are chronic, relapsing disorders for which there are few effective treatments. Changes in frontal and sub-cortical neural circuitry following prolonged drug exposure can last for years after cessation and may compromise an addict's ability to suppress drug seeking when exposed to drug- related cues. Attentional Bias Modification (ABM) training purportedly reduces the attentional response to salient drug stimuli and has been shown to be efficacious in treating alcohol dependence; however, the efficacy of ABM in treating individuals with cocaine addiction has yet to be empirically determined. Previous research suggests that chronic cocaine users also exhibit a decreased neuronal response during inhibitory control in addition to the enhanced neuronal response to salient drug cues. Preliminary neuroimaging data obtained during our R03-ISTART grant supports both lines of research, as individuals with cocaine abuse and dependence (CCA) exhibited increased activation in response to realistic cocaine cues and a profound lack of activation during inhibitory control. Although extensive evidence of these two neuronal abnormalities exists, to date we are not aware of a study that has directly compared the differential validity of these two metrics (i.e., enhanced cue reactivity and decreased inhibitory control) for predicting relapse. Additionally, our preliminary data provides evidence of increased intrinsic neuronal activity (functional connectivity; fcMRI) within a frontal sub-cortical circuit in CCA relative to controls. Therefore, the current application has two primary objectives that are both clinically significant and highly innovative. First, we will investigate the efficacy and mechanism of action of ABM in treating cocaine addiction (Aim 1). Second, we will determine which of the three neuronal abnormality or abnormalities (i.e., enhanced cue reactivity or decreased inhibitory control or increased fcMRI) are more predictive of relapse and drug utilization (Exploratory Aim 1). To achieve these two objectives, forty treatment-seeking CCA will be randomized to one of two groups in a blinded fashion: five sessions of ABM treatment or five sessions of a similar categorization control task. All participants will complete an extensive clinical and fMRI battery pre- and post-treatment designed to measure activation during cocaine cue processing, inhibitory control, and functional connectivity. We predict that ABM will prove to be efficacious in reducing relapse and that it will exert its greatest effect on reducing fcMRI and cue reactivity within frontal (orbital frontal cortex and anterior cingulate gyrus) and sub-cortical (ventral striatum) regions implicated in addiction. We also predict that individuals with increased fcMRI within frontal, sub-cortical circuits at baseline will be more likely to relapse, suggesting that repeated exposure to cocaine stimuli may result in changes in the underlying circuitry that are independent of exposure to drug stimuli. The goals of this study are clinically significant as they will potentially provide a new treatment for CCA or, at a minimum, examine whether increased fcMRI, enhanced cue reactivity or decreased inhibitory control are more predictive of relapse. PUBLIC HEALTH RELEVANCE: Chronic cocaine abuse and dependence are associated with major medical, neurological, social and interpersonal complications for the individual, their support network, and society as a whole. There are only a few effective treatments for cocaine abuse and dependence, and the development of more powerful treatments is crucial. Addicts tend to be more sensitive to cues associated with drug use and have a decreased ability to inhibit impulses to use drugs, both of which can be measured using behavioral and neuroimaging techniques such as functional magnetic resonance imaging (fMRI). Attentional Bias Modification (ABM) therapy trains individuals to divert their attention away from cues associated with drug use and has been shown to be effective in alcohol addiction. We will investigate the efficacy of ABM for treating cocaine addiction and use fMRI to identify brain changes associated with treatment effect. We will also identify brain changes that are most predictive of relapse from our collected measures. All of these goals will provide a better understanding of the neurobiological causes of addictive behavior, its chronic relapsing nature, and will contribute directly to finding effective treatments.