Prediction error governs pharmacologically induced amnesia for learned fear.

Although reconsolidation opens up new avenues to erase excessive fear memory, subtle boundary conditions put constraints on retrieval-induced plasticity. Reconsolidation may only take place when memory reactivation involves an experience that engages new learning (prediction error). Thus far, it has not been possible to determine the optimal degree of novelty required for destabilizing the memory. The occurrence of prediction error could only be inferred from the observation of a reconsolidation process itself. Here, we provide a noninvasive index of memory destabilization that is independent from the occurrence of reconsolidation. Using this index, we show in humans that prediction error is (i) a necessary condition for reconsolidation of associative fear memory and (ii) determined by the interaction between original learning and retrieval. Insight into the process of memory updating is crucial for understanding the optimal and boundary conditions on reconsolidation and provides a clear guide for the development of reconsolidation-based treatments.