Responsive Neurostimulation for Post-Traumatic Stress Disorder

项目摘要/摘要 难治性创伤后应激障碍(PTSD)的特点是恐惧消退失败和 生物底物，杏仁核对创伤的反应13，14.数十年的研究澄清了 协调恐惧消退和巩固的神经机制15。恐惧细胞和灭绝细胞 杏仁基底外侧核(BLA)根据刺激的性质和受刺激的影响改变它们的放电率。 内侧前额叶皮质(MPFC)和腹侧海马(VHPC)16、17。 VHPC形成焦虑处理网络15，2其中BLA将刺激与情绪联系起来，vHPC提供 记忆上下文，而mPFC协调消亡或巩固。局域场势(LFP)记录 从血乳酸中发现了特定的信号，这些信号对应于增强的恐惧状态。我们之前已经 显示白血球蛋白的神经调节可以促进啮齿动物模型18的灭绝，并在治疗中- 难治性创伤后应激障碍患者19。这一行动很可能是通过干扰BLA内的恐惧信号来进行的；然而， 持续的神经刺激也可能扰乱杏仁核的正常功能。本申请 建议调查六(6)名退伍军人使用反应性神经刺激(RNS，NeuroPace)的情况 患有严重的难治性创伤后应激障碍。这种双活动装置将使我们能够长期记录 来自BLA的特定条件下的LFP，例如恐惧条件反射，暴露在创伤提醒中，以及 情绪记忆的编码和检索。此外，神经活动将在现实生活中被捕捉到 闪回和噩梦的症状。这些记录将为我们提供特定的电生理 高度警惕和重新体验的生物标记物。然后，该设备将被编程为检测和治疗 这些生物标记物带有预先确定的电脉冲。将对患者进行前瞻性的随访，使用 心理量表，也有功能神经成像和脑电。这些模式将 用于确定作为治疗结果的电路连接的程度。通过从一个 从恐惧处理机制的角度来看，我们的项目将作为其他电路的概念验证- 精神病学的基础疗法。这项提案是一项涉及11名调查人员的多部门努力。 跨7个科室，需要临床和基础科学家之间的密切合作。作为一名 结果，我们慢性录音背后的发现将架起恐惧条件作用的基础科学结果的桥梁 创伤后应激障碍患者临床神经过程的研究

Project Summary/Abstract Post-traumatic stress disorder (PTSD) refractory to treatment is marked by failure of fear extinction and its biological substrate, amygdala reactivity to trauma reminders13,14. Decades of research have clarified the neuronal mechanisms coordinating fear extinction and consolidation15. Fear cells and extinction cells in the basolateral amygdala (BLA) alter their firing rate based on the nature of the stimulus and the influence from the medial prefrontal cortex (mPFC) and the ventral hippocampus (vHPC)16,17. Together, the BLA, mPFC, and the vHPC form an anxiety-processing network15,2 where the BLA links stimulus to emotion, the vHPC provides memory context, and the mPFC coordinates extinction or consolidation. Local field potential (LFP) recordings from the BLA have revealed specific signals that correspond to an enhanced fear state. We have previously shown that neuromodulation of the BLA can promote extinction in a rodent model18 and in a treatment- refractory PTSD patient19. This action is likely carried by disrupting fear signals within the BLA; however, continuous neurostimulation may also disrupt normal function of the amygdala. The present application proposes to investigate the use of Responsive Neurostimulation (RNS, Neuropace) in six (6) veterans suffering from severe treatment-resistant PTSD. This dual-activity device will allow us to chronically record LFPs from the BLA under specific conditions such as fear conditioning, exposure to trauma reminders, and emotional memory encoding and retrieval. In addition, the neural activity will be captured during real-life symptoms of flashback and nightmares. These recordings will provide us with the specific electrophysiological biomarkers of hypervigilance and re-experiencing. The device will then be programmed to detect and treat these biomarkers with a pre-determined electrical pulse. The patients will be followed prospectively using psychological scales but also with functional neuroimaging and electroencephalograms. These modalities will be used to determine the extent of circuit engagement as a result of the therapy. By approaching PTSD from a fear processing mechanism perspective, our project will serve as a proof of concept for other circuit- based therapies in psychiatry. This proposal is a multi-departmental effort involving 11 investigators across 7 departments and requires a close collaboration between clinical and basic scientists. As a result, the findings underlying our chronic recordings will bridge the basic science results from fear conditioning research to clinical neural processes in PTSD patients.