Role of prediction error in destabilizing fear memories in retrieval extinction and its neural mechanisms

Memory reconsolidation interference has been shown to be an effective way to neutralize conditioned fear memory and prevent relapse. The critical factor to utilize this paradigm is inducing a labile state of the long-term memory. Novel information is viewed as a driving factor to update memory; however, it is unknown whether different forms of novelty play the same role. In addition, although pharmacological intervention studies have confirmed that prediction error (PE) during reactivation is a necessary condition in memory destabilization, the role of PE in retrieval extinction has remained under debate; furthermore, the neural mechanisms underlying the process are largely unknown. In this study, we isolated two forms of novelty: PE and stimulus novelty without PE during reactivation to compare their role in memory lability. Skin conductance responses (SCR) and functional magnetic resonance imaging (fMRI) were used to clarify their role at the behavioural and neural mechanism levels. A total of 54 healthy adults were tested in a three-day retrieval extinction protocol. The results showed that PE, the novelty of CS-US combinations, was a critical condition to destabilize memory. The novelty of the stimulus itself with the absence of PE was insufficient for retrieving the memory. The neural mechanisms that distinguished standard extinction from retrieval extinction were that the latter was associated with a diminished recruitment of the inferior temporal cortex (IT) and dorsolateral prefrontal cortex (dlPFC) and decreased functional connectivity of the dlPFC-anterior cingulate cortex (ACC) and IT-dlPFC. Possible interpretations were discussed.