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酗酒高危人群的中枢神经系统特征。许多酗酒老兵在服兵役期间开始酗酒，退伍军人管理局负责照顾他们。尽管有大量关于酒精中毒的临床文献，但人们对这种疾病最高风险人群的临床前特征知之甚少。为了应对这种信息缺失，我们启动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虐待年轻人。有阳性家族史的人患酒精使用障碍的可能性是没有家族史的人的四倍，而且这种风险在也有反社会特征的人中加倍。双胞胎收养研究表明，酗酒的倾向、不受约束的行为和反社会行为特征是共同遗传的。因此，既有阳性家族史又有个人行为去抑制证据的人被认为是未来酗酒的高风险者，而那些缺乏这些因素的人被认为是低风险者。我们的主要假设是，高危人群已经改变了大脑机制，这些机制服务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叶皮质之间的通讯发生了变化，但缺乏确凿的神经成像。这项应用包括两个目标：Aim I解决与酒精中毒的高风险相关的改变的情感反应性，并专注于杏仁核功能连接和预期情感反应。我们发现，在观看情绪面孔的高危人群中，杏仁核活动不足表明，对社交线索的情感反应可能存在缺陷。这一发现的一个有意义的扩展是对比杏仁核功能连接性的风险组。高危人群对情感暗示的处理不充分可能与从事危险行为并使自己遭受饮酒负面后果的倾向一致。我们将使用杏仁核作为包括岛叶、背侧ACC和腹内侧PFC的网络的起点，来检查特定连接的组间差异。杏仁核对情绪面孔的激活不足提出了这样一个问题，即这种激活差异有多普遍。因此，受试者将接受一项任务，即在巴甫洛夫条件反射范式中，探索大脑对预期积极、消极或中性结果的反应。这提供了使用更大范围的刺激对情绪反应的第二个探测。我们预测，高危受试者在预期负面结果时，杏仁核的相对激活较少，而在预期尾状核、杏仁核、ACC和岛叶的结果为阳性时，相对激活较大。AIM II通过利用执行功能、决策和行为调节的三个任务来解决与酒精中毒高风险相关的行为的不受抑制的调节。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、背外侧前额叶皮质和左侧中央前下沟认知控制区的功能变化敏感。使用延迟折扣任务来检查扩展的杏仁核、伏隔核、尾状核、腹内侧额前皮质和腹侧前扣带回的功能，以检验高风险的决策。行为去抑制将通过一个停止信号任务来检验，该任务检查扣带回前部、前额叶背外侧皮质和左侧中央前下沟的认知控制区。计划中的研究有望获得有关情绪刺激处理改变和未来酗酒高危年轻人行为去抑制的新信息。

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.