Neural substrates of emotion: Impact of childhood trauma and cocaine dependence

 描述（由申请人提供）：社会压力可导致可卡因依赖（CD）个体的药物渴望和复发。此外，CD患者通常更喜欢使用药物而不是社交互动。此外，社交回避和缺乏信任是有效治疗的重大障碍。目前，没有FDA批准的药物用于治疗可卡因依赖，行为干预在维持戒断方面的成功有限。来自使用血氧水平依赖（BOLD）功能磁共振成像（fMRI）的人类神经成像研究的数据表明，“自上而下”的前额叶皮层控制杏仁核对社会刺激的反应在调节情绪相关行为中起着重要作用。在CD受试者休息时发现前额叶皮层和杏仁核之间的功能连接失调，皮质边缘功能连接减弱与复发时间缩短相关。因此，皮质边缘网络活动失调可能强调了CD个体对社会压力的脆弱性。此外，恢复前额叶皮层和杏仁核之间的功能连接，并减弱自下而上杏仁核驱动的干预措施可能会减少焦虑，改善CD患者的治疗结果。催产素（OT）是一种抗焦虑神经肽，可降低杏仁核对厌恶性社会线索的反应。此外，OT增加了广泛性社交焦虑症患者杏仁核和前额皮质之间的功能连接。该提案的广泛和长期目标是：（1）确定控制CD个体对社会刺激的情绪反应的神经生物学机制;（2）利用这些数据促进行为障碍和疾病的有效治疗和预防策略的发展。为了实现这些目标，我们提出了两个具体目标：具体目标1：确定可卡因依赖和催产素的影响，在急性社会压力皮质边缘脑区之间的功能连接。具体目标二：使用内隐面部情感识别范式来确定可卡因依赖和催产素对杏仁核活动的影响，以应对恐惧的面孔。在中性面孔期间测量的BOLD信号将从在恐惧面孔期间测量的BOLD信号中减去。为了解决与特定目标1和2相关的假设，我们提出了一项双盲安慰剂（PBO）对照研究，使用BOLD fMRI测量（1）蒙特利尔成像应激任务（MIST）期间的皮质边缘功能连接和（2）CD个体（CD n=80）和健康非依赖对照组对内隐面部情感识别范式的杏仁核活动（HC，n=80）。扫描前，受试者将接受鼻内OT（24 IU）或PBO喷雾剂（每个治疗组n=40）。使用杏仁核作为种子区域的心理生理相互作用（PPI）分析将用于评估显著任务（应激条件>对照条件）X种子相互作用。将在基线和每次运行MIST后收集主观焦虑和渴望数据。任务的顺序将被平衡。

 DESCRIPTION (provided by applicant): Social stress can lead to drug craving and relapse in cocaine-dependent (CD) individuals. In addition, CD individuals often favor drug use over social interactions. Moreover, social avoidance and lack of trust are significant obstacles to effective treatment. Currently, there are no FDA approved medications for the treatment of cocaine dependence and behavioral interventions have had limited success in sustaining abstinence. Data from human neuroimaging studies using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) suggest that "top-down" prefrontal cortical control of amygdala reactivity to social stimuli plays an important role in mediating emotion related behavior. Dysregulation in the functional connectivity between the prefrontal cortex and amygdala has been found in CD subjects at rest and attenuated corticolimbic functional connectivity was associated with a shorter time to relapse. Thus, dysregulation in corticolimbic network activity may underscore the vulnerability of CD individuals to social stress. In addition, interventions that restore functional connectivity between the prefrontal cortex and amygdala, and attenuate bottom-up amygdala drive may reduce anxiety and improve treatment outcomes for CD individuals. Oxytocin (OT) is an anxiolytic neuropeptide that reduces amygdala reactivity to aversive social cues. In addition, OT increases functional connectivity between the amygdala and prefrontal cortex in patients with generalized social anxiety disorder. The broad and long-term objectives of this proposal are to (1) to identify the neurobiologic mechanisms that control emotional responses to social stimuli in CD individuals and (2) use these data to facilitate the development of effective therapeutic treatments and preventative strategies for behavioral disorders and disease. To meet these objectives we propose two specific aims: Specific Aim 1: To determine the impact of cocaine dependence and oxytocin on functional connectivity between corticolimbic brain regions during acute social stress. Specific Aim 2: Use an implicit facial affect recognition paradigm to determine the impact of cocaine dependence and oxytocin on amygdala activity in response to fearful faces. The BOLD signal measured during neutral faces will be subtracted from the BOLD signal measured during fearful faces. To address the hypotheses associated with Specific Aims 1 and 2 we propose a we propose a double-blind placebo (PBO) controlled study using BOLD fMRI to measure (1) corticolimbic functional connectivity during the Montreal Imaging Stress Task (MIST) and (2) amygdala activity in response to an implicit facial affect recognition paradigm in groups of CD individuals (CD n=80) and healthy non-dependent controls (HC, n=80). Prior to the scanning session, participants will receive either intranasal OT (24 IU) or PBO spray (n=40 per treatment group). Psychophysiologic interaction (PPI) analysis using the amygdala as the seed region will be used to assess significant task (stress condition > control condition) x seed interactions. Subjective anxiety and craving data will be collected at baseline and after each run of the MIST. The order of the tasks will be counterbalanced.