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: 9856882
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9856882
• 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; Structure; 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.

动机的干扰是大量退伍军人功能效果不佳的主要决定者 精神分裂症（SCZ）和躁郁症（BPD）。动机被定义为定向和充满活力 预期奖励对认知和行为的影响。尽管它们具有明显的公共健康意义，但 这些严重精神疾病（SMI）的动机障碍的可用治疗方法最少 有效的。为了在治疗发展方面取得进展，更好地理解了不同的子 需要动机的组成部分会导致这些疾病中的功能障碍。在最近 完成了绩效奖，我们启动了一项翻译的情感神经科学研究计划 SCZ。使用行为和电生理范式，我们发现SCZ患者表现完好 对奖励的立即回应，但使用奖励信息适应性指导的能力降低了 行为（例如，决策，认知控制）。 对于此续约，我们建议以三种关键方式扩展这项翻译研究计划。首先，我们会的 从受影响的动机神经科学模型中检查四个子组件 将有关奖励的信息转化为自适应社区功能。这些组件及其钥匙 相关的大脑区域是：（a）奖励收据（腹侧纹状体），对奖励的直接反应，（b） 奖励预期（腹侧纹状体和眶额皮质），是指对预测的响应 提示，（c）努力价值（腹侧纹状体和背扣带回皮层），努力成本的计算 相对于增加的奖励收益，以及（d）更复杂的目标指导行动选择，其中涉及 响应奖励（腹侧纹状体）和 有效调节这些反应（背外侧前额叶皮层）以获得有价值的结果。第二，我们 将扩展我们的方法论以包括行为和fMRI任务，使我们能够更直接地“挖掘”到 动机灾难的神经元相关。第三，我们将扩展超越SCZ，以检查BPD， SMI的另一种形式具有相反的动机模式：而SCZ与不反应性相关 奖励处理的某些方面，BPD与奖励的过度反应性有关，即使在稳定中也是如此 不急性情绪发作的患者。 在这项为期四年的研究中，我们将使用SCZ（n = 60）或BPD（n = 60）招募稳定的门诊退伍军人 不在情绪发作中，匹配健康对照（n = 60）。参与者将完全验证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激活和连通性分析集中于先验定义的目标区域。 假设基于我们的初步研究以及SCZ中的动机的可用数据/理论模型 和BPD。结果将有助于指定有助于激励性的基于大脑的奖励处理障碍 干扰，并指导新治疗的临床和临床前研究。