Responsive Neurostimulation for Post-Traumatic Stress Disorder

响应性神经刺激治疗创伤后应激障碍

• 批准号: 10022169
• 负责人: Jean-Philippe Langevin
• 金额: $ 81.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10022169
• 关键词: Acute; Affect; Alpha Rhythm; American; Amygdaloid structure; Animals; Anxiety; Basic Science; Behavior Disorders; Behavioral; Bilateral; Biological; Biological Markers; Brain region; Cells; Chronic; Clinical; Collaborations; Coupling; Cues; Deep Brain Stimulation; Detection; Devices; Electrodes; Electroencephalogram; Electroencephalography; Electrophysiology (science); Emotional; Emotions; Extinction (Psychology); Failure; Frequencies; Fright; Goals; Hippocampus (Brain); Human; Hyperactive behavior; Imagery; Implant; Laboratories; Laboratory Finding; Life; Link; Measures; Medial; Memory; Metabolic; Modality; Nature; Neurons; Nightmare; Patients; Physiologic pulse; Physiological; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Productivity; Psychiatry; Quality of life; Refractory; Research; Research Personnel; Resistance; Rodent; Safety; Scientist; Serious Adverse Event; Signal Transduction; Stimulus; Symptoms; System; Time; Trauma; Veterans; anxiety reduction; base; biomarker-driven; clinical effect; clinical efficacy; conditioned fear; design; experience; experimental study; fluorodeoxyglucose positron emission tomography; follow-up; high risk; improved; memory encoding; memory recall; memory retrieval; neural network; neuroimaging; neuroregulation; next generation; post-traumatic symptoms; programs; prospective; psychologic; reduce symptoms; relating to nervous system; suicidal risk; trauma exposure; treatment effect

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.

项目总结/摘要 创伤后应激障碍（PTSD）难治性的特点是恐惧消退失败， 生物基质，杏仁核对创伤的反应性13，14。几十年的研究已经澄清了 协调恐惧消退和巩固的神经机制15.恐惧细胞和灭绝细胞 基底外侧杏仁核（BLA）根据刺激的性质和来自刺激的影响改变其放电率。 内侧前额叶皮层（mPFC）和腹侧海马（vHPC）16、17。BLA、mPFC和 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，和mPFC协调灭绝或巩固。局部场电位（LFP）记录 已经揭示了特定的信号，对应于增强的恐惧状态。我们先前已经 表明BLA的神经调节可以促进啮齿动物模型18和治疗中的消退。 难治性PTSD患者19.这一行动可能是通过扰乱BLA内部的恐惧信号来进行的;然而， 连续的神经刺激也可能破坏杏仁核的正常功能。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个双重活动装置可以让我们长期记录 特定条件下BLA的LFP，例如恐惧条件反射，暴露于创伤提醒， 情绪记忆的编码和提取此外，神经活动将在现实生活中被捕获 闪回和噩梦的症状这些记录将为我们提供 过度警觉和重新体验的生物标志物。该设备将被编程，以检测和治疗 这些生物标志物与预先确定的电脉冲。患者将接受前瞻性随访， 心理量表，功能性神经成像和脑电图。这些模式将 用于确定治疗后回路接合的程度。通过从一个 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建议是一项涉及11名调查员的多部门工作 这需要临床和基础科学家之间的密切合作。作为 结果，我们的慢性记录的基础研究结果将连接恐惧条件反射的基础科学结果 研究创伤后应激障碍患者的临床神经过程。