Reward System Function as a Potential Mediator of the Impact of Stress on Psychopathology: A Computational Neuroimaging Study

7.项目摘要 众所周知，童年创伤和最近的压力性生活事件都会导致 加重精神疾病的症状。然而，压力源发挥这些作用的潜在机制 影响尚不清楚。该项目的总体目标是研究候选神经元 特别是将压力性生活事件与精神病症状联系起来的途径。有强有力 早期生活中的逆境可以增加对以后生活中急性压力的反应。这种效应被认为是 由投射到关键额叶和皮质下结构的脑多巴胺通路的“敏化”介导。 然而，早期生活和急性压力都被证明会降低对奖励的反应性， 经验，也是。我们将研究连接额叶、边缘系统和皮层下的特定回路 结构-特别是涉及奖励和其他显著刺激和事件处理的回路-可能 在累积的压力暴露和积极和消极的症状之间的中介关系 精神病另一个目标是研究大脑如何对急性压力源做出反应，以及 早期生活逆境导致的大脑变化，在精神病的范围内各不相同。 在追求这些目标时，我们将使用临床评估工具，自我报告措施，实验行为 范例（包括急性应激诱导的范例）、计算建模和功能性磁共振成像。 核磁共振成像（fMRI）。我们还将从研究参与者那里获得生态瞬时评估， (EMA)自然主义的压力，奖励和症状，在日常生活中遇到和经历。我们 将招募164名个体的样本，由三个子样本组成：82名精神分裂症患者或 情感性精神障碍，41名精神分裂症患者的一级亲属和41名健康志愿者。是 预期来自这样的样本的参与者将具有一系列阳性和阴性症状。 我们认为这项工作很重要，因为它的目的是促进更好地了解 终身和急性应激影响精神病理学的机制，从而有助于NIMH的 其使命是“确定复杂疾病的机制”。拟议的项目是非常一致的 与NIMH的战略计划，因为它寻求联系生物学的进步-我们对生物学的理解增加， 特定的额叶皮层下和边缘电路的功能作用，特别是-与主要的环境 已知影响精神障碍的因素：压力。最后，预计这项工作的结果将 告知我们开发用于预测精神病风险和病程的生物标志物的能力， 药物和非药物干预在精神病患者中的应用。

7. Project Summary It is well-established that both childhood trauma and stressful recent life events can bring about and worsen the symptoms of mental illness. However, the underlying mechanisms by which stressors exert these effects remain unclear. The overarching goal of the proposed project is to investigate candidate neural pathways linking stressful life events to the symptoms of psychotic illness, in particular. There is strong evidence that early-life adversity can increase reactivity to acute stress later in life. This effect is believed to be mediated by “sensitization” of brain dopamine pathways projecting to critical frontal and subcortical structures. However, both early-life and acute stress have been shown to reduce responsivity to rewards and positive experiences, as well. We will investigate how specific circuits connecting frontal, limbic, and subcortical structures – especially circuits involved in the processing of rewards and other salient stimuli and events – may mediate relationships between cumulative stress exposure and both the positive and negative symptoms of psychotic illness. Another goal is to examine how brain responses to acute stressors, as well as the effects of brain changes resulting from early-life adversity, vary across the spectrum of psychotic illness. In pursing these goals, we will use clinical assessment tools, self-report measures, experimental behavioral paradigms (including those for the induction of acute stress), computational modeling, and functional Magnetic Resonance Imaging (fMRI). We will also obtain, from study participants, ecological momentary assessments (EMA) of naturalistic stressors, rewards, and symptoms, as encountered and experienced in everyday life. We will enroll a sample of 164 individuals, made up of three subsamples: 82 individuals with schizophrenia or schizoaffective disorder, 41 first-degree relatives of schizophrenia patients, and 41 healthy volunteers. It is expected that participants from such a sample will have a range positive and negative symptoms. We regard this work as important, in that it is designed to contribute to a better understanding of the mechanisms by which both lifetime and acute stress impact psychopathology, thus contributing to the NIMH's stated mission of “defining the mechanisms of complex disorders.” The proposed project is strongly aligned with the strategic plan of the NIMH, in that it seeks to link advances in biology – our increased understanding of the functional roles of specific frontal-subcortical and limbic circuits, in particular – with a major environmental factor known to influence mental disorders: stress. Finally, it is expected that the results of this work would inform our ability to develop biomarkers for prediction of psychosis risk and course, and to use pharmacological and non-pharmacological interventions in individuals with psychotic illness.