Addressing the generalization problem in neural models of fear

情绪是人类认知最重要的方面之一。无论是跳伞的刺激，喜剧表演的娱乐，还是冥想的宁静，情感往往是本质上令人向往的状态。在极端情况下，它们也可能是不受欢迎的，甚至是令人衰弱的，例如在无法控制的恐惧或焦虑的情况下。情绪也通过影响人们的记忆、感知、思想、行为和决定，在人类心理的各个方面发挥作用。对情绪理解的探索刺激了对大脑中情绪表征的研究。这项研究对情绪有了相当大的洞察力，但也得出了一些明显相互矛盾的结果：不同的大脑区域根据背景以及科学家对此进行研究的方式，激活了同一情绪状态的不同区域。以恐惧为例。由于恐惧是一种古老的情感，在动物和人类中都很常见，所以最初是在动物模型中进行研究的。因此，起初，人们对恐惧的神经科学的大部分了解都是基于对非人类动物的研究，特别是啮齿动物，这些动物被置于危险的环境中，而科学家记录了自主反应(例如心率、出汗)和防御行为(例如冻结或逃跑)。这项研究发现了一个以大脑的一部分(杏仁核)为中心的激活的大脑区域网络，最初被称为“恐惧回路”。基于动物研究的这些结果，这一环路也被认为是人类主观体验或恐惧感觉的基础。为了发现情况是否如此，使用功能磁共振成像(FMRI)的非侵入性神经成像研究被用来检查人类在恐惧时的大脑活动。这项研究的最大好处是，人类受试者可以简单地告诉科学家，他们是否真的对某些刺激感到恐惧。然而，这些人类神经成像研究的结果与动物研究的结果大不相同。在人类中，预测和体验恐惧的大脑区域广泛分布在整个大脑中。令人惊讶的是，在这些研究中，杏仁核和“恐惧回路”中的其他区域并没有被激活。这些明显相互矛盾的结果引发了许多新的问题。如果人类和动物的恐惧背后的大脑区域不同，并取决于所使用的任务、测量方法和方法，如何才能对恐惧进行统一的科学解释，从而将任何特定研究的特殊性概括为日常生活中各种不同的恐惧？对不同结果的一种可能解释可能是，早期的人类神经成像研究在描绘关键大脑区域的激活方面不够精确，这些区域在调节恐惧方面很重要。包括杏仁核、下丘脑和中脑导水管周围灰质在内的“恐惧环路”的组成部分是大脑的小核团，每个核团都由几个亚区组成。正是在这些小脑核的水平上，恐惧和防御行为的回路被组织起来。在这个项目中，研究人员使用了功能更强大的功能磁共振扫描仪，其空间分辨率比之前的神经成像研究更高，以更详细地检查这些大脑区域和与恐惧相关的大脑激活模式。参与者被诱导在许多不同的情况下感到恐惧，使用视频和疼痛威胁(但不是实际的疼痛)。大脑活动、主观自我报告的恐惧和自主神经活动的高分辨率记录都是同时获得的。这一丰富的数据集为研究主观恐惧和自主神经活动如何与大脑所有部分的活动有关提供了基础，包括“恐惧回路”中关键皮质下结构的亚区。该项目还包括分析，以确定主观恐惧和自主神经活动(如心率、皮肤电反应)的测量相一致的大脑状态。这些相关性揭示了自主神经测量是否可以用作人类恐惧感觉的指数，从而提供了关于非人类动物研究的功能同源发现是否可以推广到人类的主观恐惧体验的信息。这可能会调和动物和人类研究的结果，并导致对恐惧的神经机制的更深入理解，并为缓解恐惧和焦虑症的治疗提供启示。作为对研究项目的补充，该项目还包括一系列更广泛的影响，包括为来自服务不足社区的当地高中生举办的夏季研讨会，内容涉及恐惧和情绪的神经科学，以及克服恐惧和焦虑的方法。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Emotions are one of the most important aspects of human cognition. Whether it’s the thrill of sky diving, the amusement of a comedy show, or the serene tranquility of meditation, emotions are often intrinsically desirable states. In the extreme, they can also be undesirable or even debilitating, such as in cases of uncontrollable fear or anxiety. Emotions also play a role in perhaps every aspect of human psychology by influencing people’s memories, perceptions, thoughts, behaviors, and decisions. The search for an understanding of emotions has stimulated research on the representation of emotions in the brain. This research has lead to considerable insight into emotions, but also has lead to some apparently conflicting results: different brain regions were activated for the same emotional state depending on the context, and how scientists studied it. Take fear, for example. Since fear is an ancient emotion, common to animals as well as humans, it was originally studied in animal models. Thus, at first, most of what was understood about the neuroscience of fear was based on studies in non-human animals, particularly rodents, who were placed in threatening circumstances while scientists recorded autonomic responses (e.g. heart rate, sweating) and defensive behaviors (e.g. freezing or escape). This work uncovered a network of activated brain regions centered on a part of the brain (the amygdala), and was initially called a “fear circuit”. Based on these results from animal research, this circuit was also proposed to underlie human subjective experiences or feelings of fear. To discover if this was the case, non-invasive neuroimaging studies using fMRI (functional magnetic resonance imaging) were used to examine brain activity during fear in humans. Of great advantage to this research was that the human subjects could simply tell scientists whether they in fact felt fear in response to certain stimuli. However, the results from these human neuroimaging studies were quite different than the results from animal research. In humans, the brain regions predicting and experiencing fear were widespread and highly distributed throughout the brain. Strikingly, the amygdala and other areas in the “fear circuit” were not activated in these studies. These apparently conflicting results stimulated many new questions. If the brain regions underlying fear are different in humans and animals, and depend on the tasks, measurements, and methods that are used, how can a unified scientific account of fear be developed that generalizes across the particularities of any specific study to the diverse variety of fears in everyday life? One possible explanation of the divergent results could be that the early neuroimaging studies in humans were not precise enough in delineating activation of key brain areas that are important in mediating fear. Components of the “fear circuit” including the amygdala, hypothalamus, and periaqueductal gray are small brain nuclei and each are composed of several subregions. It is at the level of these small brain nuclei that circuits for fear and defensive behaviors are organized. In this project, researchers use a more powerful fMRI scanner, with greater spatial resolution that previous neuroimaging studies in order to examine these brain regions and the pattern of fear-related brain activation in greater detail. Participants are induced to feel fear in many distinct situations using both videos and threat of pain (but no actual pain). High resolution recordings of brain activity, subjective self-reported fear, and autonomic activity are all obtained simultaneously. This rich dataset provides a basis for studying how subjective fear and autonomic activity both relate to activity in all parts of the brain, including the subregions of key subcortical structures in the “fear circuit”. This project also includes analyses to identify brain states where subjective fear and measures of autonomic activity (such as heart rate, galvanic skin response) coincide. These correlations reveal whether autonomic measures can be used as indices for human feelings of fear, and thus provide information about whether functionally homologous findings from studies in non-human animals may generalize to subjective experiences of fear in humans. This may reconcile the results from animal and human research and lead to a deeper understanding of the neural mechanisms of fear, with implications for treatments to alleviate fear and anxiety disorders. Complementing the research project, this project also includes an extensive set of broader impacts including a summer workshop for local high school students from underserved communities on the neuroscience of fear and emotion, and ways of overcoming fear and anxiety.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.