Neuroimaging in the Oklahoma Family Health Patterns Project

描述（由申请人提供）： 我们的长期目标是更好地了解有酗酒风险的人的中枢神经系统特征。许多退伍军人酗酒开始大量饮酒期间，他们在军队服役，退伍军人事务部负责他们的照顾。尽管有大量关于酒精中毒的临床文献，但对最有可能患上这种疾病的人的临床前特征知之甚少。为了应对这种信息缺失，我们制定了俄克拉荷马州家庭健康模式项目，以研究有和没有酗酒家族史的非滥用年轻人。有阳性家族史的人发展酒精使用障碍的可能性是没有这种历史的人的四倍，并且这种风险在也有反社会特征的人中加倍。双胞胎收养的研究表明，酗酒倾向，放纵和反社会的行为特征是共同遗传的。同时具有阳性家族史和行为抑制解除的个人证据的人相应地被认为是未来酒精中毒的高风险，而缺乏这些因素的人被认为是低风险。我们的主要假设是，高风险的人已经改变了大脑机制，这些机制有助于对环境产生正常的情绪反应，并且对公开行为的调节不足。虽然有证据表明边缘系统和前额皮质之间的交流发生了变化，但缺乏证实性的神经影像学。这个应用程序被归入两个目标：目标I地址改变与酗酒的高风险相关的情感反应，并专注于杏仁核功能连接和预期的情感反应。我们发现，高风险人群在看到情绪化面孔时杏仁核功能低下，这表明他们对社会线索的情感反应可能存在缺陷。这一发现的一个有意义的延伸是对比杏仁核功能连接的风险组。高风险人群对情感线索的处理不足可能与他们从事危险行为的倾向以及饮酒的负面后果相一致。我们将研究特定连接中的组差异，使用杏仁核作为网络的起点，包括杏仁核，背侧ACC和腹内侧PFC。杏仁核对情绪面孔的低激活提出了一个问题，即这种激活差异有多普遍。因此，受试者将接受一项任务，在巴甫洛夫条件反射范式中探测大脑对预期积极、消极或中性结果的反应。这提供了使用更广泛刺激的情绪反应的第二个探测器。我们预测，高风险受试者在预期负面结果时杏仁核的相对激活较少，而在预期正面结果时杏仁核的相对激活较大：尾状核，杏仁核、前扣带和杏仁核。目标二解决了与酗酒高风险相关的行为的去抑制调节，使用三个任务，挖掘执行功能，决策和行为调节。执行控制将使用Stroop反应冲突任务进行测试，该任务对前扣带回、背外侧前额叶皮层和左下中央前沟的认知控制区域的功能改变敏感。风险决策的检查使用延迟折扣任务检查功能的扩展杏仁核，核，尾状核，腹内侧前额叶皮层，腹侧前扣带回。将通过停止信号任务检查前扣带回、背外侧前额叶皮质和左下中央前沟的认知控制区域，检查行为去抑制。计划中的研究预计将产生新的信息，改变处理情绪刺激和行为抑制的年轻人在未来酗酒的高风险。 公共卫生相关性： 与退伍军人健康的相关性治疗酒精中毒是退伍军人管理局系统的主要医疗保健费用。酒精中毒通常表现在18-30岁的人中（Babor，Hofmann等人，1992年），这一时间恰逢服兵役，也许是战斗暴露。因此，退伍军人管理局系统负责大量退伍军人的酒精和其他物质使用障碍，开始在现役期间。对酒精中毒高危人群的研究可以增加我们对前因因素的了解，有助于建立酒精中毒发展模型，并有助于预测谁的风险最大。

DESCRIPTION (provided by applicant): Our long-term goal is to develop a better understanding of central nervous system characteristics of persons at risk for alcoholism. Many Veteran alcoholics begin heavy drinking during their time in military service, and the VA is responsible for their care. Despite a large clinical literature on alcoholism, far less is known about the preclinical characteristics of persons at greatest risk for the disorder. In response to this information deficit, we instituted the Oklahoma Family Health Patterns Project to study nonabusing young adults with and without a family history of alcoholism. Persons with a positive family history are four times as likely to develop alcohol use disorders as those with no such history, and this risk doubles in persons who also have antisocial characteristics. Twin-adoption studies show that a tendency toward alcoholism and disinhibited and antisocial behavior traits that are coinherited. Persons with both a positive family history and personal evidence of behavioral disinhibition are accordingly considered to be at High Risk of future alcoholism, and those lacking these factors are considered at Low Risk. Our major hypothesis is that High Risk persons have altered brain mechanisms that serve to produce normal emotional responses to the environment and have deficient regulation of overt behavior. While evidence points to altered communication between the limbic system and prefrontal cortex, confirmatory neuroimaging is lacking. This application is subsumed under two aims: Aim I addresses altered affective reactivity associated with a high risk for alcoholism, and focuses on amygdala functional connectivity and anticipatory affective responses. Our discovery of amygdalar hypoactivation in High Risk persons viewing emotional faces suggests a possible deficit in affective response to social cues. A meaningful extension of this finding is to contrast the risk groups in functional amygdala connectivity. Inadequate processing of affective cues in High Risk persons may be consistent with a tendency to engage in risky behaviors and to subject themselves to negative consequences of drinking. We will examine group differences in specific connections, using the amygdala as the starting point of a network that includes the insula, the dorsal ACC, and the ventromedial PFC. The presence of amygdalar hypoactivation to emotional faces raises the question of how general this activation difference is. Therefore subjects will undergo a task that probes brain responses to anticipation of positive, negative, or neutral outcomes in a Pavlovian conditioning paradigm. This provides a second probe of emotional responsivity using a wider range of stimuli. We predict that the High Risk subjects will have less relative amygdala activation in anticipation of negative outcomes and greater relative activation in anticipation of positive ones in: caudate n., amygdala, ACC, and the insula. Aim II addresses disinhibited regulation of behavior associated with a high risk for alcoholism using three tasks that tap executive function, decision-making, and behavioral regulation. Executive controls will be tested using the Stroop response conflict task, sensitive to altered function in the cognitive control regions of the anterior cingulate gyrus, dorsolateral prefrontal cortex, and the left inferior precentral sulcus. Risky decision-making is examined using a delay discounting task examining functioning of the extended amygdala, nucleus accumbens, caudate, ventromedial prefrontal cortex, and ventral anterior cingulate gyrus. Behavioral disinhibition will be examined with a stop-signal task examining cognitive control regions of the anterior cingulate gyrus, dorsolateral prefrontal cortex, and the left inferior precentral sulcus. The planned studies are expected to yield new information concerning altered processing of emotional stimuli and behavioral disinhibition in young adults at high risk for future alcoholism. PUBLIC HEALTH RELEVANCE: Relevance to Veterans Health Treatment of alcoholism is a major health care cost for the VA system. Alcoholism often manifests in persons 18-30 years of age (Babor, Hofmann et al., 1992), a time that coincides with military service and perhaps combat exposure. As a result, the VA system is responsible for large numbers of veterans with alcohol and other substance use disorders that began during the period of active military service. Studies of persons at elevated risk for alcoholism can increase our knowledge of antecedent factors, contribute to models of alcoholism development, and aid in predicting who is most at risk.