Intracranial Neural Mechanisms of Fear Response in Humans with and without Anxiety-Related Disorders

项目摘要/摘要 从啮齿动物研究中积累的证据表明，恐惧的表达来自于 包括腹内侧额叶皮质(VmPFC)在内的神经网络内的电生理变化， 基底外侧杏仁核(BLA)和前海马区(AHPC)5。目前尚不清楚该网络是否表现出 人类在与恐惧相关的状态中的类似动态以及在不适当的情况下这种活动是如何改变的 通常在患有焦虑相关障碍的个体中观察到的恐惧表达，如创伤后 应激障碍(PTSD)或广泛性焦虑症(GAD)。拟议的研究将调查 脑深部活动(颅内脑电和单个单位)与生理学的关系 植入者的反应(皮肤电导反应、瞳孔大小和心率/变异性) 微丝电极用于临床评估和治疗癫痫患者将完成虚拟现实恐惧 条件反射任务。在项目期间，这项研究将接触到25名有或没有参加的罕见参与者 焦虑症(即创伤后应激障碍和/或广泛性焦虑症) 通过持续的合作，在vmPFC、BLA和/或HPC中植入深度电极 加州大学洛杉矶分校的临床和基础科学领导者和退伍军人管理局大洛杉矶医疗保健 系统。由于我们的研究解决了围绕vmPFC-BLA-aHPC动力学在 调节恐惧反应，这是精神疾病中经常受到影响的一个过程，预计研究结果将 几十年来人类和动物恐惧相关研究的桥梁，并为改进 对焦虑症的认识和治疗。 除了完成上述研究外，我还将接受广泛的专业和学术培训，以 为我的终极目标--成为一名神经外科医生和科学家--做好准备。这将包括从Basic开始的指导 侵入性人体记录兼容实验的科学家专家(南西亚·苏萨纳博士)和高级 统计分析(Jonathan Kao博士)除了神经外科医生提供的临床和调查指导外- 科学家(让·菲利佩·朗之万博士)。通过与这些人以及我的资深合作者一起工作 (米歇尔·克拉斯克博士和迈克尔·范斯洛博士)，我将学习设计与临床相关的行为实验， 记录侵入性人类神经生理学，获取神经科学和神经解剖学方面的专业知识，实现 高度发展的信号处理和统计分析技能，并磨练了我的临床，写作和 演讲技巧。

PROJECT SUMMARY/ABSTRACT Accumulating evidence from rodent studies suggests that the expression of fear emerges from electrophysiological changes within a neural network that includes the ventromedial prefrontal cortex (vmPFC), basolateral amygdala (BLA), and anterior hippocampus (aHPC)5. It is unclear whether this network exhibits similar dynamics during fear-related states in humans and how this activity is altered during inappropriate expression of fear that is often observed in individuals with anxiety-related disorders such as post-traumatic stress disorder (PTSD) or generalized anxiety disorder (GAD). The proposed study will investigate the relationship between deep brain activity (intracranial electroencephalographic and single unit) and physiological response (skin conductance response, pupil size, and heart rate/variability) in humans who are implanted with microwire electrodes for clinical evaluation and treatment of epilepsy who will complete a virtual reality fear conditioning task. Over the project period, the study will have access to 25 rare participants with and without anxiety disorders (i.e. post-traumatic stress disorder [PTSD] and/or generalized anxiety disorder [GAD]) implanted with depth electrodes in the vmPFC, BLA, and/or aHPC through an ongoing collaboration between clinical and basic science leaders at UCLA and the Veteran’s Administration Greater Los Angeles Healthcare System. Since our studies address basic questions surrounding the role of vmPFC-BLA-aHPC dynamics in regulating fear response, a process often compromised in psychiatric disease, it is anticipated that findings will bridge decades of human and animal fear-related research and lay the scientific foundation for improved understanding and treatment of anxiety-related disorders. In addition to completing the described research, I will undergo extensive professional and academic training to prepare me for my ultimate-goal of becoming a neurosurgeon-scientist. This will include mentorship from basic scientist experts in invasive human recording compatible experiments (Dr. Nanthia Suthana) and high level statistical analysis (Dr. Jonathan Kao) in addition to clinical and investigative guidance from a neurosurgeon- scientist (Dr. Jean Phillipe Langevin). Through working with these individuals along with my senior collaborators (Drs. Michelle Craske and Michael Fanselow), I will learn to design clinically relevant behavioral experiments, record invasive human neurophysiology, obtain expert knowledge in neuroscience and neuroanatomy, achieve a highly developed skillset for signals processing and statistical analysis and hone my clinical, writing, and presentation skills.