Affective Neuroscience of Motivation in Schizophrenia and Bipolar Disorder

精神分裂症和双相情感障碍动机的情感神经科学

• 批准号: 10426241
• 负责人: Jonathan Wynn
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426241
• 关键词: Acute; Anterior; Award; Base of the Brain; Behavior; Behavioral; Bipolar Disorder; Brain region; Clinical; Clinical Research; Clinical assessments; Cognition; Cognitive; Communities; Complex; Cues; Data; Decision Making; Disease; Dorsal; Electrophysiology (science); Functional Magnetic Resonance Imaging; Goals; Impairment; Incentives; Methodology; Modeling; Moods; Motivation; Neurosciences Research; Outcome; Outpatients; Participant; Patient Self-Report; Patients; Pattern; Performance; Plant Roots; Prefrontal Cortex; Productivity; Public Health; Reaction Time; Research; Research Project Grants; Rewards; Sampling; Schizophrenia; Signal Transduction; Specific qualifier value; Testing; Theoretical model; Translating; Translational Research; Ventral Striatum; Veterans; affective neuroscience; base; behavioral response; cingulate cortex; cognitive control; cognitive process; functional disability; functional outcomes; improved functioning; indexing; interest; neural correlate; pleasure; preclinical study; programs; prospective; recruit; relative cost; response; reward anticipation; reward processing; severe mental illness; therapy development; translational research program

Disturbances in motivation are major determinants of poor functional outcome in a large number of Veterans with schizophrenia (SCZ) and bipolar disorder (BPD). Motivation is defined as the orienting and energizing impact of prospective rewards on cognition and behavior. Despite their clear public health significance, available treatments for motivational disturbances in these serious mental illnesses (SMIs) are minimally effective. To make progress in treatment development, a much better understanding of how different sub- components of motivation contribute to functional impairment in these disorders is needed. In a recently completed Merit award, we launched a translational affective neuroscience research program on motivation in SCZ. Using behavioral and electrophysiological paradigms, we found that SCZ patients showed intact immediate responses to rewards, but a diminished ability to use reward information to adaptively guide behavior (e.g., decision making, cognitive control). For this renewal, we propose to extend this translational research program in three key ways. First, we will examine four sub-components from an affective neuroscience model of motivation that are critical for translating information about rewards into adaptive community functioning. These components and their key associated brain regions are: (a) Reward Receipt (ventral striatum), the immediate response to rewards, (b) Reward anticipation (ventral striatum & orbitofrontal cortex), which refers to responsivity to reward predicting cues, (c) Effort valuation (ventral striatum & dorsal anterior cingulate cortex), the computation of effort costs relative to increasing reward benefits, and (d) more complex Goal-directed action selection, which involves reciprocal capacities to energize higher level cognitive processes in response to rewards (ventral striatum) and to effectively regulate these responses (dorsolateral prefrontal cortex) to obtain valued outcomes. Second, we will extend our methodology to include behavioral plus fMRI tasks, enabling us to more directly “dig down” into the neural correlates of motivational disturbances. Third, we will expand beyond SCZ to also examine BPD, another form of SMI with an opposing pattern of motivation: whereas SCZ is associated with hypo-reactivity in certain aspects of reward processing, BPD is associated with hyper-reactivity to rewards – even in stabilized patients who are not in an acute mood episode. In this 4-year study, we will recruit stabilized outpatient Veterans with SCZ (n = 60) or BPD (n = 60) who are not in a mood episode, and matched healthy controls (n = 60). Participants will complete validated fMRI motivation tasks and corresponding behavioral motivation tasks, as well as clinical assessments of community functioning. fMRI activation and connectivity analyses focus on a priori defined regions of interest. Hypotheses are based on our preliminary studies and available data/theoretical models of motivation in SCZ and BPD. Results will help specify brain-based reward-processing impairments that contribute to motivational disturbances, and guide both clinical and preclinical studies of new treatments.

动机障碍是导致大量退伍军人功能不良的主要因素 精神分裂症（SCZ）和双相情感障碍（BPD）。动机被定义为导向和激励 预期奖励对认知和行为的影响。尽管它们具有明显的公共卫生意义， 这些严重精神疾病（SMI）中动机障碍的现有治疗方法是最低限度的 有效为了在治疗开发方面取得进展，需要更好地了解不同的亚组如何 动机的组成部分有助于这些疾病的功能障碍是必要的。的情形发生在每一 完成优异奖后，我们启动了一项关于动机的转化情感神经科学研究计划， SCZ。使用行为和电生理学范式，我们发现SCZ患者表现出完整的 对奖励的即时反应，但使用奖励信息自适应引导的能力减弱 行为（例如，决策、认知控制）。 对于这次更新，我们建议以三种关键方式扩展这一转化研究计划。一是 研究动机的情感神经科学模型中的四个子成分，这些子成分对 将奖励信息转化为适应性社区功能。这些组件及其关键 相关的大脑区域是：（a）奖励接收（腹侧纹状体），对奖励的即时反应，（B） 奖励预期（腹侧纹状体和眶额皮层），指对奖励预测的反应性 线索，（c）努力评价（腹侧纹状体和背侧前扣带皮层），努力成本的计算 相对于增加奖励收益，以及（d）更复杂的目标导向行动选择，其中涉及 对奖励（腹侧纹状体）做出反应时激发更高水平认知过程的相互能力， 有效地调节这些反应（背外侧前额叶皮层），以获得有价值的结果。二是 将扩展我们的方法，包括行为加上功能磁共振成像任务，使我们能够更直接地“挖掘”到 动机紊乱的神经关联第三，我们将扩展到SCZ之外，也检查BPD， 另一种形式的SMI具有相反的动机模式：而SCZ与低反应性有关， 在奖励处理的某些方面，BPD与对奖励的过度反应有关-即使在稳定的情况下， 没有急性情绪发作的患者。 在这项为期4年的研究中，我们将招募稳定的门诊退伍军人与SCZ（n = 60）或BPD（n = 60）谁是 没有情绪发作，并匹配健康对照组（n = 60）。参与者将完成经验证的fMRI 动机任务和相应的行为动机任务，以及社区的临床评估 功能fMRI激活和连接分析集中在先验定义的感兴趣区域。 假设是基于我们的初步研究和现有的数据/理论模型的动机在SCZ 和BPD。研究结果将有助于明确大脑的奖励处理障碍，这些障碍有助于激励 干扰，并指导新治疗的临床和临床前研究。