Brain Imaging Studies of Negative Reinforcement in Humans

描述（由申请人提供）：治疗药物成瘾的一个主要挑战是了解与厌恶性成瘾者的习得性联系如何促进回避行为并引发药物使用的发作和复发。对非人类动物的研究已经开始阐明回避学习的神经行为机制，但很少有人将这些发现转化为人类。支持长期记忆形成的神经可塑性大脑机制被假设为改变刺激的表征并根据其激励特性加强上下文关联。该研究采用认知神经科学的观点来描述动机脑系统如何调节人类陈述性记忆的形成并导致行为回避。虽然人类陈述性记忆传统上是使用列表学习范式探测，但计算机图形界面和沉浸式虚拟现实（VR）技术的最新进展允许开发新的导航回避任务，这些任务提供了与动物文献的更紧密联系，并更紧密地模拟了吸毒成瘾者在应对环境压力时表现出的现实世界回避行为。健康参与者将接受一系列功能性磁共振成像研究，这些研究在传统的列表学习和基于VR的导航学习和记忆任务的背景下呈现强化刺激。第一系列实验比较了食欲和厌恶工具性记忆对陈述性记忆系统的影响。第二系列的实验确定了负面情绪状态如何放大工具性记忆者的激励属性的记忆效应，并激励寻求奖励（“救济”）作为一种情绪修复形式。第三系列的实验开发了一个多感官，沉浸式VR范式，模拟压力诱导的回避和逃避自然主义的记忆任务，结合导航和列表学习方法。功能连接模型，结合多元回归和独立成分分析，将表征动机和记忆系统的相互作用，以及它们与行为表现指数和回避特质标记的个体差异的关系。因此，拟议的研究代表了人类回避学习的系统和创新方法，结合了尖端的VR技术和功能性神经成像方法。这些研究结果将弥合理解积极行为者，情绪状态和压力源如何修改厌恶行为后果对学习和记忆系统的影响的翻译差距，帮助建立环境显着特征的内部地图。 公共卫生相关性：在药物成瘾中，环境压力源的经历和回忆可以触发药物使用的发作和复发，作为逃避生活挑战的手段。这项拟议中的研究将通过促进对厌恶性行为如何调节大脑记忆系统和促进回避行为的理解来影响公共卫生。该研究还开发了新的范例，可以纳入临床试验，以评估奖励如何缓解负面情绪，并使用虚拟现实模拟评估压力学习环境中的逃避行为。

DESCRIPTION (provided by applicant): A major challenge to treating drug addiction is understanding how learned associations to aversive reinforcers promote avoidant behavior and trigger the onset and relapse of drug use. Studies in non-human animals have begun to elucidate the neurobehavioral mechanisms of avoidance learning, but there have been few efforts to translate these findings to human populations. Neuroplastic brain mechanisms that support long-term memory formation are hypothesized to alter the representations of stimuli and strengthen contextual associations as a function of their incentive properties. The proposed research adopts a cognitive neuroscience perspective to characterize how motivational brain systems modulate declarative memory formation in humans and lead to behavioral avoidance. Although human declarative memory is traditionally probed using list- learning paradigms, recent advances in computer graphics interfaces and immersive virtual reality (VR) technology permit the development of novel navigational avoidance tasks that provide a tighter link with the animal literature and more closely model real-world avoidant behaviors exhibited by drug addicts in response to environmental stressors. Healthy participants will undergo a series of functional magnetic resonance imaging studies that present reinforcing stimuli within the context of both traditional list-learning and novel VR-based navigational learning and memory tasks. The first series of experiments compares the influence of appetitive versus aversive instrumental reinforcers on declarative memory systems. The second series of experiments determines how negative mood states amplify the mnemonic effects of the incentive properties of instrumental reinforcers and motivate reward-seeking ("relief") as a form of mood repair. The third series of experiments develops a multisensory, immersive VR paradigm that simulates stress-induced avoidance and escape on a naturalistic memory task that combines navigational and list-learning approaches. Functional connectivity modeling, in combination with multiple regression and independent components analyses, will characterize the interactions of motivational and memory systems and their relationship to individual differences in behavioral performance indices and trait markers of avoidance. The proposed studies thus represent a systematic and innovative approach to human avoidance learning that combines cutting-edge VR technology and functional neuroimaging methods. The research findings will bridge a translational gap in understanding how positive reinforcers, mood states, and stressors modify the impact of aversive behavioral consequences on learning and memory systems that help establish internal maps of salient features of the environment. PUBLIC HEALTH RELEVANCE: In drug addiction, the experience and recall of environmental stressors can trigger the onset and relapse of drug use as a means to escape from life challenges. The proposed research will impact public health by advancing an understanding of how aversive reinforcers modulate memory systems in the brain and promote avoidant behavior. The research also develops new paradigms that could be incorporated into clinical trials to assess how rewards provide relief from negative moods, and to assess escape behavior in a stressful learning context using virtual reality simulations.