Drug Abuse, Social Decision-Making, and Sex-Related Functional Brain Asymmetry

描述(申请人提供)：本研究申请是对#RFA-DA-06-004的回应。毒品和酒精滥用的核心是糟糕的决策，特别是在应对社会影响时。这种决策缺陷使人高度联想起神经内侧前额叶皮质(VMPC)受损的神经科患者的社会决策障碍。VMPC患者提供了一个社会决策失误的神经学模型。临床前和临床水平都有证据表明，VMPC是药物滥用的关键大脑区域，我们认为VMPC功能障碍和社会决策缺陷可能是滥用药物和酒精成瘾的个体的特征。在这项研究应用中，我们计划在神经科患者中进行研究，以充实社会决策的神经生物学基础，利用独特的爱荷华州患者注册表，该注册表包含数千名患者的神经心理学和神经解剖学数据。一个特别的重点是性别差异。我们有一个有趣的初步发现，表明在VMPC和社会决策之间的关系中可能存在一个与性别相关的重要差异：在男性中，右侧的VMPC可能是关键的，而在女性中，左侧的VMPC可能是关键的。这些实验将测试三个具体目标：(1)使用最后通牒游戏、信任游戏、爱荷华州赌博任务和Ellsberg任务等任务，确定VMPC在社会决策方面是否存在性别相关的功能不对称；(2)将与性别相关的功能不对称的研究扩展到其他已知对与决策相关的社会和情感过程至关重要的大脑结构，即杏仁核和岛叶皮质；(3)通过对早期VMPC受损的患者的研究，调查VMPC与社会决策和情绪处理之间的关系的发展影响。这些实验将提供有关社会决策和情绪处理的神经生物学基础的重要新信息。与药物滥用的联系是直接的：VMPC患者的决策缺陷与吸毒者、酗酒者和成瘾者(“近视未来”)有着惊人的相似之处。因此，我们的研究可以帮助精确定位神经功能障碍的来源，这些神经功能障碍有助于做出以药物和酒精滥用为特征的糟糕决策。与公共健康相关：这项研究将帮助我们了解大脑的不同部分对社会决策和情绪处理是如何重要的，这些大脑-行为关系是否存在性别差异，以及这些关系是如何发展的。这项研究可以帮助为药物和酒精滥用障碍的治疗和预防提供信息，以及社会行为障碍、人格障碍和焦虑和情绪障碍，所有这些都与药物和酒精滥用有很高的共患率。

DESCRIPTION (provided by applicant): This research application is in response to #RFA-DA-06-004. At the heart of drug and alcohol abuse is bad decision-making, especially in response to social influences. This decision-making defect is highly reminiscent of the social decision-making impairments that characterize neurological patients with damage to ventromedial prefrontal cortex (VMPC). The VMPC patients provide a neurological model of social decision- making gone awry. There is evidence at both preclinical and clinical levels that the VMPC is a key brain region in drug abuse, and we propose that VMPC dysfunction and defective social decision-making may characterize individuals who abuse and become addicted to drugs and alcohol. In this research application, we plan to conduct studies in neurological patients in order to flesh out the neurobiological underpinnings of social decision-making, taking advantage of the unique Iowa Patient Registry that contains neuropsychological and neuroanatomical data for thousands of patients. A particular focus is on gender differences. We have intriguing preliminary findings suggesting that there might be an important sex-related difference in the relationship between the VMPC and social decision-making: in men, the right VMPC might be critical, whereas in women, the left VMPC might be critical. The experiments will test three specific aims: (1) To determine whether there is sex-related functional asymmetry of the VMPC in regard to social decision- making, using tasks such as the Ultimatum Game, Trust Game, Iowa Gambling Task, and Ellsberg Tasks; (2) To extend the investigation of sex-related functional asymmetry to other brain structures known to be critical for social and affective processes related to decision-making, namely, the amygdala and the insular cortex; (3) To investigate developmental influences on the relationship between the VMPC and social- decision making and emotional processing, by studying patients who incurred VMPC damage early in life. The experiments will furnish important new information about the neurobiological underpinnings of social decision-making and emotional processing. The link with substance abuse is direct: the decision-making deficits in VMPC patients have striking similarities with those evident in drug and alcohol abusers and addicts ("myopia for the future"). Thus, our research could help pinpoint sources of neural dysfunction that contribute to bad decision-making of the type that characterizes drug and alcohol abuse. Public health relevance: This research will help us understand how various parts of the brain are important for social decision-making and emotional processing, whether there are gender differences in these brain- behavior relationships, and how these relationships develop. The research could help inform treatment and prevention of drug and alcohol abuse disorders, as well as social conduct disorders, personality disorders, and anxiety and mood disorders, all of which have high comorbidity with drug and alcohol abuse.