Developing Methods for Brain Stimulation Enhanced Fear Reversal in PTSD

描述（由申请人提供）：对非人类动物大脑回路的电、化学和基因操作，使我们对习得性恐惧是如何获得的，如何被消除（通过与矛盾证据的经验减少），以及在某些情况下，尽管有证据表明恐惧的厌恶事件不会再发生，但恐惧记忆如何持续引发压力反应的理解取得了重要进展。在人类创伤后应激障碍（PTSD）的案例中，证据表明恐惧记忆持续存在，并且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到的恐惧记忆消失保留的神经生物学基础证据一致。通过在恐惧消失的背景下操纵人类的相同电路，它可能是

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.