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

项目摘要 神经调节正在成为精神病学的新前沿。我们在理解的最新进展 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 以恢复正常功能。经颅磁刺激(TMS)为无创治疗提供了一种很好的工具 操纵这样的电路。尽管TMS取得了一些巨大的临床成功，并将其应用于精神病学 条件，TMS如何影响恐惧电路的机制目前还不清楚，它的参数 就业情况没有得到充分优化。我们的目标是1)了解不同的TMS参数如何影响 2)优化其在增强恐惧消退记忆巩固方面的影响 有已知恐惧消退缺陷的人群：创伤后应激障碍(PTSD)。和所有人一样 操作，并不是所有参与者都会对TMS做出反应，TMS导致的恐惧减少会因不同而不同 研究对象。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 根据条件性和非条件性恐惧的大小以及临床和焦虑测量。 受试者将在3天内接受我们公认的恐惧条件反射和消亡范例。在第一天， 他们通常会受到两种提示的制约。在第二天，受试者将接受灭绝训练， 条件性线索将以一种时间和解剖学上的特定方式与TMS配对。在第三天， 有条件的提示将出现在功能磁共振扫描仪中。被调查的网络是恐惧消亡 环路：腹内侧前额叶皮质(VmPFC)、背侧前扣带回皮质(DACC)、海马体和 杏仁核。皮肤电导反应(SCR)也将被测量。我们将探索狭隘的影响 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 关于激活记忆的恐惧消退网络。我们的目标是背外侧前额叶皮质(Dlpfc)。 其在功能上与VMPFC相耦合。利用响应面方法(RSM)的原理，我们 将表征和确定TMS的时间和解剖变异相对于 条件性减少恐惧的条件性提示(目标1)。然后，我们将使用优化的TMS参数来测试 TMS能否恢复创伤后应激障碍受试者的消退记忆缺陷(目标2)。探索性的目标将是 开发数学模型来预测TMS在获得消退记忆的最佳结果方面的成功 根据SCR和临床数据。我们的发现将为应用知识提供关键的翻译数据 从啮齿动物身上收集到人脑中，可以帮助我们理解神经调节的机制 关于创伤后应激障碍患者恐惧消退网络神经相关因素的变化。

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.