Testing a Memory-Based Hypothesis for Anhedonia

项目总结 快感缺乏症--从通常令人愉快的刺激中体验快乐的能力减弱--是一种 多种精神疾病的跨诊断症状，包括抑郁症、精神分裂症和精神分裂症后 创伤性应激障碍。近期快感缺乏症研究的快速增长是由其令人震惊的临床研究推动的 陈述：快感缺乏独立地与自杀风险增加、治疗抵抗和 生活质量下降。严重抑郁障碍和精神分裂症--以快感缺失为主要特征的障碍 症状--与与巨额医疗费用相关的越来越高的经济负担有关 和失业问题。目前，快感缺乏症还没有明确的生物学定义。因此，临床医生依赖于 自我报告的衡量标准与其潜在的神经生物学没有明确的联系。在行为上 在快感缺乏症中观察到奖赏加工缺陷和奖赏回路功能障碍。 奖励反应经常被保存下来，这表明对经验价值的记忆可能是 妥协了。这就引出了这一提议的核心问题：快感缺乏在多大程度上是一种记忆 有问题吗？我们建议测试基于记忆的快感缺乏症，作为我们生物学定义的目标的一部分 构造物。我们注意到，虽然记忆不太可能是快感缺失的唯一基础(当然有 明确的经验方面)，它可能是一个未被研究和被认可的球员。关键的是，一个定义明确的 记忆贡献可以帮助确定新的治疗目标，并为改进临床实践铺平道路 具有生物信息的决策能力。我们使用计算精神病学的方法，结合 使用先进的神经成像和人工智能工具对新范例中的行为进行数学建模以识别和 验证与预防和治疗快感缺乏相关的生物标志物。我们统一了计算模型 价值、强化学习和情景记忆，跨越正价和正价的RDoC域 认知系统。我们的目标是：(1)测试快感缺乏对价值调节情节记忆的影响，以及 其神经机制的高分辨率全脑功能磁共振成像；(2)测试快感缺失对记忆的影响- 使用高分辨率全脑功能磁共振成像指导奖励决策和相关的神经机制； (3)测试快感缺乏对结构和功能连通性测量以及自主神经的影响 监管。我们还将使用AI/ML工具来创建快感缺乏症的预测生物标志物的多模式库。 我们的最终目标是开发一个全面的、机械的和可操作的基于内存的帐户 快感缺乏症使用新的范式、计算模型、高分辨率神经成像以及人工 开发新的干预措施和改进临床实践的智能方法。

PROJECT SUMMARY Anhedonia—the diminished capacity to experience pleasure from normally pleasurable stimuli—is a transdiagnostic symptom of multiple psychiatric disorders, including depression, schizophrenia and post- traumatic stress disorder. The recent and rapid growth of anhedonia research is fueled by its alarming clinical presentation: anhedonia is independently associated with increased risk of suicide, treatment resistance, and reduced quality of life. Major depressive disorder and schizophrenia—disorders of which anhedonia is a cardinal symptom—are linked with increasingly high levels of economic burden related to substantial health care costs and unemployment. There is currently no clear biological definition of anhedonia. As a result, clinicians rely on self-report measures with no clear established connection to its underlying neurobiology. While behavioral reward processing deficits and dysfunctional reward circuitry have been observed in anhedonia, in-the-moment reward responding is frequently preserved, suggesting that memory for the value of the experience may be compromised. This prompts the central question of this proposal: to what extent is anhedonia a memory problem? We propose to test a memory-based account for anhedonia as part of our goal to biologically define the construct. We note that while it is unlikely that memory is the only basis for anhedonia (certainly there are clear experiential aspects), it may be an understudied and underappreciated player. Critically, a well-defined memory contribution can help identify novel treatment targets and pave the path to improving clinical practice with biologically informed decision-making. We use a computational psychiatry approach, combining mathematical modeling of behavior in novel paradigms with advanced neuroimaging and AI tools to identify and validate biomarkers relevant to the prevention and treatment of anhedonia. We unite computational models of value, reinforcement learning, and episodic memory, bridging across the RDoC domains of Positive Valence and Cognitive Systems. Our aims are to: (1) Test the impact of anhedonia on value-modulated episodic memory and its neural mechanisms using high-resolution whole brain fMRI; (2) Test the impact of anhedonia on memory- guided decisions for reward and the associated neural mechanisms using high-resolution whole brain fMRI; and (3) Test the impact of anhedonia on structural and functional connectivity measures as well as autonomic regulation. We will also use AI/ML tools to create a multimodal library of predictive biomarkers for anhedonia. Our ultimate goal is to develop a comprehensive, mechanistic, and actionable memory-based account for anhedonia using new paradigms, computational models, high-resolution neuroimaging, as well as artificial intelligence approaches to develop novel interventions and improve clinical practice.