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: 10651814
• 负责人: Mohammed R Milad
• 金额: $ 74.15万
• 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/10651814
• 关键词: Affect; Amygdaloid structure; Anatomy; Anterior; Anxiety; Brain; Brain region; Clinical; Clinical Data; Collection; Conditioned Reflex; Coupled; Cues; Data; Dorsal; Effectiveness; Extinction; Fright; Functional Magnetic Resonance Imaging; Galvanic Skin Response; Genetic Complementation Test; Hippocampus; 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; cingulate cortex; 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领域的新领域。我们最近在理解方面的进步 涉及恐惧及其法规的神经回路为我们提供了明确的目标和电路来操纵 恢复正常功能。经颅磁刺激（TMS）为非侵入性提供了一个很好的工具 操纵这样的电路。尽管在TMS上有一些巨大的临床成功及其在精神科中的应用 条件，TMS如何影响恐惧电路的机制尚不理解及其参数目前 雇用尚未完全优化。我们的目标是1）了解不同的TMS参数如何影响 有针对性的大脑区域为2）优化其对增强恐惧灭绝记忆巩固的影响 具有已知恐惧灭绝不足的人群：创伤后应激障碍（PTSD）。和所有人一样 操纵，并非所有参与者都会对TMS做出反应，而TMS引起的恐惧会有所不同 主题。探索性目标是开发数学模型来预测谁将对TMS做出响应 基于条件和无条件的恐惧以及临床和焦虑措施的大小。 受试者将在3天内经历我们公认的恐惧调节和灭绝范式。在第1天， 他们将厌恶到两个提示。在第2天，受试者将接受灭绝培训 条件提示将以时间和解剖学特定方式与TMS配对。在第3天， 条件提示将在功能磁共振成像扫描仪中介绍。要调查的网络是恐惧灭绝 电路：腹侧前额叶皮层（VMPFC），背扣带回皮层（DACC），海马和 杏仁核。皮肤电导反应（SCR）也将进行测量。我们将探索狭窄的影响 TMS定时差异（相对于条件恐惧刺激的发作）和恐惧灭绝时的解剖位置 在激活恐惧灭绝网络上的记忆。我们的目标将是背外侧前额叶皮层（DLPFC） 这在功能上与VMPFC结合。使用响应表面方法（RSM）的原理，我们 将表征并确定TMS相对于TMS的时间和解剖学变化的影响 有条件提示减少恐惧（AIM 1）。然后，我们将使用优化的TMS参数进行测试 如果TMS可以恢复具有PTSD受试者的灭绝记忆不足（AIM 2）。探索目的是 开发数学模型，以预测TMS在获得灭绝记忆中获得最佳结果的成功 基于SCR和临床数据。我们的发现将提供应用知识的关键翻译数据 从啮齿动物聚集到人脑，可以帮助我们了解神经调节的机制 关于PTSD患者恐惧灭绝网络的神经相关性的变化。