Gambling Disorder: Neuroimaging of Reward and Anti-Reward Circuitry

 描述(由申请人提供)： 在退伍军人中，赌博障碍(GD)的流行率至少是普通公众的两倍，而且 与破坏性后果有关，包括高达43%的患者有自杀企图。然而，人们对这种疾病背后的神经生物学机制知之甚少，而这些知识可能对开发成功的治疗干预措施至关重要。在这方面，药物成瘾模型具有启发性价值，因为在第5版《精神疾病诊断和统计手册》中，GD被归类为“物质相关和成瘾障碍”。吸毒和赌博成瘾的特点都是对天然强化剂的敏感度降低，以及类似压力的情绪状态。在药物成瘾中，这种症状被归因于各自的“奖赏缺乏”和“反奖赏”平衡神经适应。在目前的方案中，我们试图通过整合功能磁共振成像(FMRI)、认知心理学和精神药理学来测量40名GD退伍军人和40名健康退伍军人的奖赏和应激反应，以确定GD是否存在类似的神经适应。作为第二个对照组，我们将招募40名患有可卡因使用障碍(CUD)的退伍军人，按成瘾严重程度与GD组匹配。该项目的三个实验程序包括：(A)通过对奖励和压力图像的视觉处理来唤起社会奖励和压力，(B)静脉注射育亨宾，一种可靠地增加生理和心理压力反应的去甲肾上腺素能药物，以及(C)将金钱奖励纳入赌博任务。我们使用这些程序对GD和健康受试者进行比较的初步数据发现，在奖励和应激处理过程中，腹侧被盖、伏隔核、杏仁核、眶前皮质和豆状核下延伸杏仁核以及相关结构中的fMRI信号变化具有独特的模式。在拟议的实验中，预计与健康对照组相比，患有GD和CUD的退伍军人在奖励性和应激性刺激领域分别表现出减弱和夸大的反应。GD组的损害预计不会那么突出，与长期接触可卡因的更严重的有害影响相一致。还预测了这些神经反应与GD和CUD的临床特征之间的联系。我们的发现将有助于理解行为成瘾(GD)与物质成瘾(CUD)的不同特征，以及它们在常见成瘾过程中的独特贡献。除了为了解和预防GD的发展提供重要线索，特别是在慢性应激暴露的背景下，我们的项目还将对情绪麻木和压力敏感症状的发病机制提供见解，这些症状不仅会导致成瘾患者严重残疾，而且还会导致其他神经精神疾病，如创伤后应激障碍、精神分裂症和严重抑郁。

 DESCRIPTION (provided by applicant): In Veterans, gambling disorder (GD) is at least twice as prevalent as in the general public, and it is associated with devastating outcomes including suicidal attempts in up to 43% of the patients. However, little is known about the neurobiological mechanisms underlying this disorder while such knowledge may be vital for the development of successful therapeutic interventions. Drug addiction models have heuristic value in this regard as GD is classified among "Substance-Related and Addictive Disorders" in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Both drug and gambling addiction are characterized by decreased sensitivity to natural reinforcers and stress-like emotional states. In drug addiction, such symptomatology has been attributed to respective "reward deficiency" and "anti-reward" allostatic neuroadaptations. In the present proposal we seek to determine whether similar neuroadaptations exist in GD by integrating functional magnetic resonance imaging (fMRI), cognitive psychology and psychopharmacology to measure reward and stress responses in 40 Veterans with GD and in 40 healthy Veterans. As a second comparison group, we will enroll 40 Veterans with cocaine use disorder (CUD) matched to the GD group by the addiction severity. Three experimental procedures on this project include: (a) evoking social reward and stress by visual processing of rewarding and stressful images, (b) intravenous administration of yohimbine, a noradrenergic agent that reliably increases physiological and psychological stress responses and (c) monetary reward incorporated into a gambling task. Our preliminary data using these procedures to compare GD and healthy subjects identified unique patterns of fMRI signal changes in the ventral tegmentum, nucleus accumbens, amygdala, orbitofrontal cortex and sublenticular extended amygdala along with related structures during reward and stress processing. In the proposed experiments, it is predicted that, in comparison to healthy controls, Veterans with GD and CUD will exhibit diminished and exaggerated responses in the domains of rewarding and stressful stimuli, respectively. The impairments in the GD group are expected to be less prominent consistent with more severe deleterious effects of chronic cocaine exposure. An association is also predicted between those neural responses and clinical characteristics of GD and CUD. Our finding will allow understanding the distinctive features of behavioral addiction, GD, vis-à-vis those of a substance addiction, CUD, and their unique contribution to the common addictive process. In addition to providing important leads for understanding and preventing the development of GD particularly in the context of chronic stress exposure, our project will offer insights on the pathogenesis of emotional numbing and stress sensitivity symptoms, which cause severe disability not only in addicted patients, but also in those suffering from other neuropsychiatric conditions such as post-traumatic stress disorder, schizophrenia and major depression.