The Neural Basis of the Positivity Offset as a Mechanism of Avolition in Schizophrenia

项目摘要 避免（例如，减少动机和参与目标导向行为）是一个核心的负面症状， 是精神分裂症患者功能障碍的最强预测因子之一。目前的社会心理和 药物干预在治疗无意识方面是无效的，这主要是由于对它的了解有限。 基本机制。涉及功能失调的皮质-纹状体相互作用的主要概念框架 奖励处理的异常提高了该领域对病因学的理解。 然而，这项工作尚未导致治疗方面的重大突破。这些 模型假设享乐反应在精神分裂症中是完整的，我们实验室最近提出的一个理论可能是 早产通过应用Cacioppo的评价空间模型的情感科学方法， 我们最近证明，情绪体验的异常确实有助于 在精神分裂症中，以积极性偏移减少的形式。正性偏移是一种自适应的 在低唤醒水平下，积极情绪比消极情绪更平衡的功能， 促进积极的行为。我们实验室的初步数据表明， 精神分裂症，并与临床评定的阴性症状有关，这表明它可能提供了一种新的 解释avolition。在目前的研究中，我们的目标是通过以下方式扩展这些发现：1）识别神经元 作为正性偏移的基础的电路，2）确定正性偏移是否也在真实的中减小。 世界精神分裂症，和3）确定是否减少积极抵消和相关的神经 在日常生活中预测排尿的过程。具体来说，我们将使用功能磁共振成像来测量神经活动期间， 情绪体验任务，以测试假设，减少激活的内侧前额叶皮层， 脑桥核和尾状核与精神分裂症的阳性偏移减少有关。 此外，我们将研究这些区域的激活是否预示着积极性偏移减少， 在现实世界中的avolition，这将通过主动和被动的数字表型测量。这种方法 解决了情感和神经机制的基础avolition和他们的理解差距差距 影响日常运作。研究结果有可能为个性化医疗方法提供信息， 通过识别特定的神经回路和情感过程，可以作为治疗目标， 药物和心理干预。此外，很少有临床研究者接受过采用 跨学科、多模式的方法来研究阴性症状。拟议的研究和培训计划 旨在满足这一领域的迫切需求，为申请人提供尖端技术 神经影像学和数字表型分析方法来检验关于无意识起源的假设。

PROJECT SUMMARY Avolition (e.g., reduced motivation and engagement in goal-directed behavior) is a core negative symptom and one of the strongest predictors of functional disability in schizophrenia. Current psychosocial and pharmacological interventions are ineffective at treating avolition, largely due to limited understanding of its underlying mechanisms. Leading conceptual frameworks implicating dysfunctional cortico-striatal interactions and abnormalities in reward processing have improved the field's understanding of the etiological underpinnings of avolition; however, this work has not yet led to significant breakthroughs in treatment. These models assume that the hedonic response is intact in schizophrenia, a theory our lab recently proposed may be premature. By applying an affective science approach informed by Cacioppo's Evaluative Space Model of Emotional Experience, we recently demonstrated that abnormalities in emotional experience do contribute to avolition in schizophrenia, in the form of a reduction in the positivity offset. The positivity offset is an adaptive function characterized by a greater balance of positive than negative emotion at low levels of arousal, which promotes motivated behaviors. Preliminary data from our lab indicates that the positivity offset is reduced in schizophrenia and is associated with clinically rated negative symptoms, suggesting it may offer a novel explanation for avolition. In the current study, we aim to expand these findings by: 1) identifying the neural circuits underlying the positivity offset, 2) determining whether the positivity offset is also reduced in the real- world in schizophrenia, and 3) determining whether reductions in the positivity offset and associated neural processes predict avolition in everyday life. Specifically, we will use fMRI to measure neural activity during an emotional experience task to test the hypothesis that reduced activation of the medial prefrontal cortex, nucleus accumbens, and caudate nucleus is associated with reductions in the positivity offset in schizophrenia. Additionally, we will examine whether activation in these regions predicts positivity offset reduction and avolition in the real-world, which will be measured via active and passive digital phenotyping. This approach addresses the gap in understanding of the affective and neural mechanisms underlying avolition and their impact on daily functioning. Findings have potential to inform personalized medicine approaches to treating avolition by identifying specific neural circuits and affective processes that can serve as treatment targets for pharmacological and psychosocial interventions. Further, few clinical investigators are trained to adopt a transdisciplinary, multimodal approach to study negative symptoms. The proposed research and training plans are designed to meet this urgent need in the field, providing the applicant with skills in cutting-edge neuroimaging and digital phenotyping methods to test hypotheses about the origins of avolition.