Affective Neuroscience of Motivation in Schizophrenia and Bipolar Disorder

动机障碍是大量退伍军人功能不良的主要决定因素 患有精神分裂症(SCZ)和躁郁症(BPD)。激励的定义是定向和激励 预期奖励对认知和行为的影响。尽管它们对公共卫生具有明显的意义， 对这些严重精神疾病(SMI)的动机障碍的可用治疗是最低限度的 有效。为了在治疗开发方面取得进展，更好地了解不同的亚型 在这些障碍中，动机的组成部分会导致功能损害是必要的。在最近的一个 完成优秀奖，我们启动了一个关于动机的翻译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患者表现出完好无损 对奖励的即时反应，但使用奖励信息自适应指导的能力减弱 行为(例如，决策、认知控制)。 对于此次更新，我们建议在三个关键方面扩展这一翻译研究计划。首先，我们将 考察动机的情感神经科学模型中的四个子成分，它们对 将有关奖励的信息转化为适应性的社区功能。这些组件及其关键 相关的大脑区域是：(A)奖赏接收(腹侧纹状体)，即对奖赏的直接反应，(B) 奖赏预期(腹侧纹状体和眶前皮质)，指的是对奖赏预测的反应性 线索，(C)努力评估(腹侧纹状体和背侧前扣带回皮质)，努力成本的计算 相对于增加奖励福利，以及(D)更复杂的目标导向的行动选择，其中包括 对奖赏(腹侧纹状体)和刺激更高水平的认知过程作出反应的相互能力 有效地调节这些反应(背外侧前额叶皮质)以获得有价值的结果。第二，我们 将扩展我们的方法以包括行为和功能磁共振任务，使我们能够更直接地深入到 动机干扰的神经关联。第三，我们将超越SCZ，也研究BPD， 另一种形式的SMI具有相反的动机模式：而SCZ与 在奖励处理的某些方面，BPD与对奖励的高反应性有关--即使在稳定的情况下也是如此 没有急性情绪发作的患者。 在这项为期4年的研究中，我们将招募患有SCZ(n=60)或BPD(n=60)的稳定的门诊退伍军人，他们是 无情绪发作，与健康对照组(n=60)匹配。参与者将完成经过验证的功能磁共振成像 激励任务和相应的行为激励任务，以及社区的临床评估 功能正常。FMRI激活和连通性分析集中在先验定义的感兴趣区域。 假设是基于我们对SCZ动机的初步研究和现有数据/理论模型。 和BPD。结果将有助于确定有助于激励的基于大脑的奖励处理障碍 并指导新疗法的临床和临床前研究。

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.