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

奖励系统功能作为压力对精神病理学影响的潜在中介：一项计算神经影像学研究

• 批准号: 9766405
• 负责人: JAMES A WALTZ
• 金额: $ 52.72万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766405
• 关键词: Acute; Affect; Affective; Anhedonia; Attention; Behavior; Behavioral; Behavioral Paradigm; Biological; Biological Markers; Biology; Brain; Chronic; Chronic stress; Clinical; Clinical Assessment Tool; Complex; Computer Simulation; Corpus striatum structure; Diagnosis; Dimensions; Disease; Dopamine; Ecological momentary assessment; Enrollment; Environmental Risk Factor; Event; First Degree Relative; Functional Magnetic Resonance Imaging; Goals; Hyperactive behavior; Individual; Intervention; Laboratories; Lead; Learning; Life; Link; Literature; Measures; Mediating; Mediator of activation protein; Mental disorders; Midbrain structure; Mission; Modeling; Motivation; National Institute of Mental Health; Negative Valence; Neural Pathways; Outcome; Participant; Pathway interactions; Patient Self-Report; Patients; Pattern; Pharmacology; Play; Positive Valence; Psychological reinforcement; Psychopathology; Psychotic Disorders; Research Domain Criteria; Rewards; Risk; Role; Sampling; Schizoaffective Disorders; Schizophrenia; Serotonin; Severities; Signal Transduction; Stimulus; Strategic Planning; Stress; Structure; Symptoms; System; Testing; Work; acute stress; biological adaptation to stress; biomarker development; design; early life adversity; early life stress; experience; healthy volunteer; hedonic; heuristics; incentive salience; motivated behavior; neural circuit; neural model; neuroimaging; neuromechanism; neurotransmission; pediatric trauma; psychotic symptoms; relating to nervous system; response; reward processing; stressor

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.

7.项目总结 众所周知，童年创伤和最近的压力生活事件都可以带来 使精神疾病的症状恶化。然而，应激源施加这些压力的潜在机制 其影响尚不清楚。拟议项目的首要目标是研究候选神经。 尤其是将应激性生活事件与精神病症状联系起来的途径。有很强的 有证据表明，早年的逆境会增加晚年对急性压力的反应能力。这种效应被认为是 这是由投射到关键额叶和皮质下结构的大脑多巴胺通路的“敏化”所介导的。 然而，早年和急性压力都被证明会降低对奖励和积极的反应能力。 体验也是如此。我们将研究连接额叶、边缘和皮质下的特定回路 结构--尤其是涉及奖赏和其他显著刺激和事件处理的电路--可能 累积应激暴露与阳性症状和阴性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应激源做出反应，以及 早期生活中的逆境导致的大脑变化，在精神疾病的不同谱系中是不同的。 在追求这些目标的过程中，我们将使用临床评估工具、自我报告测量、实验行为 范例(包括急性应激诱导的范例)、计算模型和功能磁学 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 在日常生活中遇到和经历的自然主义压力、奖励和症状的(EMA)。我们 将招募164人的样本，由三个子样本组成：82名精神分裂症患者或 精神分裂症患者的一级亲属41名，以及健康志愿者41名。它是 预计来自这样一个样本的参与者将会有一系列阳性和阴性症状。 我们认为这项工作很重要，因为它的设计有助于更好地了解 终生应激和急性应激对精神病理的影响机制，从而导致NIMH 声明的使命是“定义复杂疾病的机制”。提议的项目是紧密结合的 与NIMH的战略计划相结合，因为它寻求将生物学方面的进展-我们对 额叶--特别是皮质下和边缘环路--的功能作用与主要环境 已知的影响精神障碍的因素是：压力。最后，预计这项工作的结果将是 告知我们开发预测精神病风险和病程的生物标记物的能力，并使用 精神病患者的药理学和非药理学干预。