State-Dependent TMS over Prefrontal Cortex Disrupts Fear-Memory Reconsolidation and Prevents the Return of Fear

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 (dIPFC) 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 dIPFC. In contrast, no decrease was observed in participants tested immediately after dIPFC-rTMS or in participants receiving either control rTMS (i.e., active control site and sham stimulations) or dIPFC-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 dIPFC-rTMS was administered within the reconsolidation time window. Moreover, dIPFC-rTMS prevented subsequent return of fear after extinction training. These findings highlight the causal role of dIPFC in fear-memory reconsolidation and suggest that rTMS can be used in humans to prevent the return of fear.