The Neurobiology of Affective Dysfunction in Schizophrenia

描述（由申请人提供）：情感功能障碍已被认为是精神分裂症的主要缺陷，而平淡情感是一种突出的阴性症状，对治疗提出了挑战。我们在当前项目中的努力通过临床、神经行为、结构和功能神经影像学方法的融合，推进了对精神分裂症情绪处理缺陷的理解。我们的研究结果强调了平坦情绪在对过程和结果产生不利影响方面的重要性。他们认为，边缘系统和前额叶区域之间的相互作用可能是情绪处理和一些认知缺陷的基础。 我们目前的研究还揭示了患者未受影响的一级亲属在情绪处理方面的实质性缺陷，并且更新申请建议研究一组未受影响的兄弟姐妹。神经科学的进步提供了前所未有的工具来探索健康人情绪处理的神经生物学，并以更高的精度揭示可能导致人类功能障碍的机制。 精神分裂症拟议的竞争性更新应用程序的目标是建立在当前的研究结果基础上，并专注于功能性MRI（fMRI）范式，以检查精神分裂症患者及其未受影响的兄弟姐妹的情绪处理。在拟议的研究中，我们将进行两个实验，都使用稀疏的事件相关的设计，可以隔离神经系统从事自上而下的情绪分类任务，从那些响应威胁相关的面部影响。在第一个实验中，我们将测试这一假设，即异常的自下而上的杏仁核反应，面部情绪特别是受损的恐惧表情，并有助于误解，并可能无法处理情感价刺激。我们将证实我们的研究结果，这种异常的杏仁核反应与严重程度的平面影响，并产生不利影响的过程和结果，并检查注视方向对边缘系统激活的影响。本实验的样本量有能力检查焦虑、基础认知和情绪处理能力、性别差异和种族效应的潜在调节效应。在第二个实验中，我们将检查变量，可以调节异常杏仁核反应的威胁相关的面部表情。我们将通过操纵面部特征中传达的信息来检查刺激参数的贡献。具体来说，我们将确定的影响，在上部或下部的脸的变化，并通过使用照片的面部情感显示熟悉的人获得的参与者。在这两个实验中，结合识别任务将允许连接边缘系统的反应，正确的面部编码的可能性。遗传策略的应用，通过研究家庭成员的神经行为和功能磁共振成像范例，将允许整合两个强大的研究策略， 精神分裂症-遗传学和行为神经科学-需要评估脆弱性。我们预计 结果揭示了精神分裂症情感功能障碍的机制， 查明脆弱性和治疗。

DESCRIPTION (provided by applicant): Affective dysfunction has been recognized as a major deficit in schizophrenia, and flat affect is a prominent negative symptom, presenting a challenge for treatment. Our efforts in the current project have advanced the understanding of emotion processing deficits in schizophrenia through convergence of clinical, neurobehavioral and structural and functional neuroimaging methods. Our results underscored the importance of flat affect in adversely impacting course and outcome. They suggested that the interaction between limbic and prefrontal regions could underlie both emotion processing and some cognitive deficits. Our current study has also revealed substantial deficits in emotion processing in unaffected first-degree relatives of patients, and the renewal application proposes to study a group of unaffected siblings. Advances in neuroscience provide unprecedented tools to probe the neurobiology of emotion processing in healthy people and reveal with increased precision mechanisms that could be responsible for dysfunction in people with schizophrenia. The goal of the proposed competing renewal application is to build on current findings and focus on functional MRI (fMRI) paradigms to examine emotion processing in people with schizophrenia and their unaffected siblings. In the proposed study we will perform two experiments, both using a sparse event-related design that can isolate neural systems engaged in top-down emotion categorization tasks from those responding to threat related facial affect. In the first experiment we will test the hypothesis that abnormal bottom-up amygdale response to facial affect is especially impaired for fearful expressions, and contributes to misinterpretation and possibly failure to process affectively valenced stimuli. We will confirm our findings that this abnormal amygdala response is strongly associated with severity of flat affect and adversely impacts course and outcome, and examine the effects of gaze direction on limbic activation. The sample size for this experiment is powered to examine potentially modulating effects of anxiety, basal cognitive and emotion processing abilities, sex differences, and ethnicity effects. In the second experiment we will examine variables that could modulate the abnormal amygdala response to threat related facial expressions. We will examine the contribution of stimulus parameters by manipulating information conveyed in facial features. Specifically, we will determine the effects of changes in upper or lower face, and familiarity by using photographs of facial affect displays obtained from people familiar to the participants. In both experiments, incorporation of a recognition task will permit linking limbic response to the likelihood of correct face encoding. The application of a genetic strategy, by studying family members with the neurobehavioral and fMRI paradigms, will permit the integration of two powerful research strategies in schizophrenia - genetics and behavioral neuroscience - needed to assess vulnerability. We expect the results to shed light on mechanisms for affective dysfunction in schizophrenia that can lead to improved identification of vulnerability and treatment.