Erasing maladaptive memories has been a challenge for years. A way to change fear memories is to target the process of reconsolidation, during which a retrieved memory transiently returns to a labile state, amenable to modification [1, 2]. Disruption of human fear-memory reconsolidation has been classically attempted with pharmacological [3] or behavioral (e.g., extinction) [4] treatments that, however, do not clarify the underlying brain mechanism. To address this issue, in 84 healthy humans submitted to six experiments, here, we combined a differential fear conditioning paradigm with repetitive transcranial magnetic stimulation (rTMS) administered in a state-dependent manner. In a critical condition, we stimulated the dorsolateral prefrontal cortex (dlPFC) 10 min after a reminder cue that reactivated a fear memory acquired 1 day before. At testing, 24 h after rTMS, participants exhibited decreased physiological expression of fear, as shown by their skin conductance response. Similar reductions were observed when targeting the left and the right dlPFC. In contrast, no decrease was observed in participants tested immediately after dlPFC-rTMS or in participants receiving either control rTMS (i.e., active control site and sham stimulations) or dlPFC-rTMS without preceding fear-memory reactivation, thus showing both the site and time specificity and state dependency of our rTMS intervention. Expression of fear was indeed reduced only when dlPFC-rTMS was administered within the reconsolidation time window. Moreover, dlPFC-rTMS prevented subsequent return of fear after extinction training. These findings highlight the causal role of dlPFC in fear-memory reconsolidation and suggest that rTMS can be used in humans to prevent the return of fear.

多年来，消除适应不良的记忆一直是一项挑战。改变恐惧记忆的一种方法是针对再巩固过程，在此过程中，检索到的记忆会暂时恢复到不稳定状态，可以进行修改 [1, 2]。经典地尝试通过药理学 [3] 或行为（例如，灭绝）[4] 治疗来破坏人类恐惧记忆的再巩固，但并未阐明潜在的大脑机制。为了解决这个问题，在提交给六个实验的 84 名健康人中，我们将差异恐惧条件反射范式与以状态相关的方式进行的重复经颅磁刺激 (rTMS) 相结合。在危急情况下，我们在提醒提示后 10 分钟刺激了背外侧前额叶皮层 (dlPFC)，该提示重新激活了 1 天前获得的恐惧记忆。在测试中，在 rTMS 后 24 小时，参与者表现出恐惧的生理表达减少，如他们的皮肤电导反应所示。当靶向左侧和右侧 dlPFC 时，观察到类似的减少。相比之下，在 dlPFC-rTMS 后立即测试的参与者或接受对照 rTMS（即主动控制部位和假刺激）或 dlPFC-rTMS 的参与者中没有观察到减少，而没有事先恐惧记忆重新激活，因此显示了部位和时间我们的 rTMS 干预的特异性和状态依赖性。只有在重新巩固时间窗口内给予 dlPFC-rTMS 时，恐惧的表达才会真正减少。此外，dlPFC-rTMS 阻止了灭绝训练后恐惧的后续回归。