Neuromodulation of the fear extinction circuit using temporally and anatomically specific TMS in humans

使用人类时间和解剖学特异性 TMS 对恐惧消退回路进行神经调节

• 批准号: 10296453
• 负责人: Mohammed R Milad
• 金额: $ 80.85万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296453
• 关键词: Affect; Amygdaloid structure; Anatomy; Anterior; Anxiety; Brain; Brain region; Clinical; Clinical Data; Collection; Conditioned Reflex; Coupled; Cues; Data; Disease model; Dorsal; Effectiveness; Extinction (Psychology); Fright; Functional Magnetic Resonance Imaging; Galvanic Skin Response; Hippocampus (Brain); Human; Hypersensitivity skin testing; Individual; Knowledge; Location; Mathematics; Measures; Memory; Memory impairment; Methodology; Modeling; Outcome; Participant; Patients; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Psychiatry; Rattus; Regulation; Rodent; Running; Sampling; Shock; Side; Statistical Models; Stimulus; Surface; Testing; Time; Training; Transcranial magnetic stimulation; Variant; anxiety sensitivity; base; cingulate cortex; clinical anxiety; conditioned fear; experimental study; frontier; indexing; interest; mathematical model; memory consolidation; neural circuit; neural correlate; neuromechanism; neuropsychiatry; neuroregulation; novel; novel strategies; outcome prediction; predictive modeling; recruit; response; success; tool

Project Summary Neuromodulation is becoming the new frontier in psychiatry. Our recent advances in the understanding of neural circuits involved in fear and its regulation provide us with a well-defined targets and circuits to manipulate to restore normal functioning. Transcranial magnetic stimulation (TMS) provides a great tool to non-invasively manipulate such circuits. Despite some great clinical success in TMS and its application to psychiatric conditions, the mechanisms of how TMS impacts fear circuits are not understood and its parameters currently employed are not fully optimized. Our objectives are to 1) understand how varying TMS parameters affect targeted brain regions in order to 2) optimize its impact on enhancing fear extinction memory consolidation in a population with known fear extinction deficiencies: posttraumatic stress disorder (PTSD). As with all manipulations, not all participants will respond to TMS and fear reduction induced by TMS will vary across subjects. An exploratory objective is to develop mathematical models for predicting who will respond to TMS based on the magnitude of conditioned and unconditioned fear along with clinical and anxiety measures. Subjects will undergo our well-established fear conditioning and extinction paradigm across 3 days. On day 1, they will be aversively conditioned to two cues. On day 2, subjects will undergo extinction training where conditioned cues will be paired with TMS in a temporally and anatomically specific manner. On day 3, conditioned cues will be presented in the fMRI scanner. The network to be investigated is the fear extinction circuit: the ventromedial prefrontal cortex (vmPFC), dorsal anterior cingulate cortex (dACC), hippocampus, and amygdala. Skin conductance response (SCR) will also be measured. We will explore the impact of narrow TMS timing variance (relative to onset of conditioned fear stimuli) and anatomical location on fear extinction memory on the activation of fear extinction network. Our target will be the dorsolateral prefrontal cortex (dlPFC) that is functionally coupled with the vmPFC. Using the principles of response surface methodology (RSM), we will characterize and establish the effect of temporal and anatomical variations of TMS relative to the conditioned cue on conditioned fear reduction (aim 1). We will then use the optimized TMS parameters to test if TMS can restore extinction memory deficit in subjects with PTSD (aim 2). An exploratory aim will be to develop mathematical models to predict TMS success in obtaining the best outcome on extinction memory based on SCR and clinical data. Our findings would provide key translational data applying knowledge gathered from rodents into the human brain and could help us understand the mechanisms of neuromodulation regarding change in the neural correlates of fear extinction network in PTSD patients.

项目摘要 神经调节正在成为精神病学的新前沿。我们最近在了解 参与恐惧及其调节的神经回路为我们提供了一个明确的目标和回路来操纵 恢复正常功能经颅磁刺激（TMS）提供了一个很好的工具， 操纵这样的电路。尽管TMS在临床上取得了一些巨大的成功， 条件下，TMS如何影响恐惧回路的机制尚不清楚，其参数目前 所使用的并不完全优化。我们的目标是1）了解不同的TMS参数如何影响 靶向大脑区域，以2）优化其对增强恐惧消退记忆巩固的影响， 一个已知有恐惧消退缺陷的人群：创伤后应激障碍（PTSD）。如同所有 然而，并非所有的参与者都会对TMS做出反应，TMS引起的恐惧减少会因不同的人而异。 科目一个探索性的目标是开发数学模型来预测谁会对TMS做出反应 基于条件性和非条件性恐惧的程度沿着临床和焦虑测量。 受试者将在3天内接受我们完善的恐惧条件反射和消退范式。在第一天， 他们会被两种暗示所厌恶。在第2天，受试者将接受灭绝训练， 条件提示将以时间上和解剖学上特定的方式与TMS配对。在第三天， 条件线索将在功能磁共振成像扫描仪中呈现。要调查的网络是恐惧灭绝 回路：腹内侧前额叶皮层（vmPFC）、背侧前扣带皮层（dACC）、海马和 杏仁核还将测量皮肤电导反应（SCR）。我们将探讨窄 TMS时间差异（相对于条件性恐惧刺激的开始）和恐惧消退的解剖位置 记忆对恐惧灭绝网络的激活。我们的目标将是背外侧前额叶皮层（dlPFC） 在功能上与vmPFC耦合。利用响应曲面法（RSM）的原理，我们 将表征并确定TMS的时间和解剖学变化相对于 条件线索对条件恐惧减少（目标1）。然后，我们将使用优化的TMS参数来测试 TMS是否可以恢复PTSD受试者的消退记忆缺陷（目标2）。一个探索性的目标将是 开发数学模型来预测TMS成功获得灭绝记忆的最佳结果 基于SCR和临床数据。我们的研究结果将提供关键的翻译数据， 从啮齿类动物收集到人类大脑中，可以帮助我们了解神经调节的机制， 关于PTSD患者恐惧消退网络神经相关物的变化。