Developing Methods for Brain Stimulation Enhanced Fear Reversal in PTSD

描述（由申请人提供）：对非人类动物脑回路的电、化学和遗传操纵使我们对学习性恐惧如何获得、如何消除（通过具有矛盾证据的经验减少）以及在某些情况下恐惧记忆如何持续引发应激反应的理解取得了重要进展，尽管有证据表明恐惧的厌恶事件不会再次发生。在人类创伤后应激障碍（PTSD）的情况下，有证据表明，恐惧记忆持续存在，这种持续存在的大脑异常的位置与从非人类动物研究中收集的恐惧记忆消退保留的神经生物学底物的证据一致。通过在人类恐惧消退的背景下操纵同样的回路， 有可能增强对学习恐惧线索的压力反应的减轻。拟议的研究旨在确定最适合使用重复经颅磁刺激（rTMS）在健康参与者中进行这种增强的参数。通过测试行为和心理生理学的反应，学习恐惧线索之前和之后灭绝结合应用rTMS多个大脑目标，每个目标在增强恐惧记忆消退的有效性将进行评估。将rTMS与神经成像（功能性磁共振成像）交叉应用于这些目标脑区将产生额外的证据，证明任务和PTSD病理生理学中涉及的关键脑回路中的诱导可塑性如何与恐惧学习和灭绝有关。在健康参与者中以这种方式评估多个目标，然后可以选择一个或多个用于诊断为PTSD的患者的测试。rTMS的有效性，从而影响行为和心理生理学反应的学习恐惧线索，将探讨在健康人群中作为一个功能的诱导可塑性机制，在这种情况下测量的第一次结合TMS/功能磁共振成像方法。从这些措施中收集的证据将为评估PTSD的神经生物学改善提供一个新的框架，也可能支持在随后的rTMS治疗中靶向特定的大脑区域。

DESCRIPTION (provided by applicant): Electrical, chemical, and genetic manipulation of brain circuitry in non-human animals has led to important advances in our understanding of how learned fear is acquired, how it is extinguished (lessened by experience with contradictory evidence), and how in some cases fear memories persist in eliciting stress reactions despite evidence that the feared aversive event will not recur. In the case of posttraumatic stress disorder (PTSD) in humans, evidence suggests that fear memories persist and the location of brain abnormalities underlying this persistence are consistent with the evidence for the neurobiological substrates of fear memory extinction retention gathered from non-human animal studies. By manipulating this same circuitry in humans in the context of fear extinction, it may be possible to augment the lessening of stress reactions to learned fear cues. The proposed study seeks to determine the parameters best suited for this augmentation in healthy participants using repetitive transcranial magnetic stimulation (rTMS). By testing behavioral and psychophysiological responses to learned fear cues before and after extinction in conjunction with applying rTMS to multiple brain targets, the effectiveness of each target in augmenting fear memory extinction will be evaluated. Applying rTMS interleaved with neuroimaging (functional magnetic resonance imaging) to these targeted brain areas will yield additional evidence of how induced plasticity in key brain circuits implicated in the task and in PTSD pathophysiology may relate to fear learning and extinction. Multiple targets will be evaluated this way in healthy participants before one or more can be selected for testing in patients diagnosed with PTSD. The effectiveness of rTMS to influence behavioral and psychophysiological responding to learned fear cues will thus be explored in healthy populations as a function of induced plasticity mechanisms measured in this context for the first time combining TMS/fMRI methods. The evidence gathered from these measures will provide a novel framework for evaluating neurobiological improvements in PTSD and may also support particular brain regions for targeting in a subsequent rTMS treatment.