Closed-loop brain stimulation to reduce pathologic fear

Abstract

Maladaptive processing of trauma related memory engrams leads to dysregulated fear reactions. In post-traumatic stress disorder (PTSD), dysfunctional extinction learning prevents discretization of trauma-related memory engrams and leads to generalized fear responses. PTSD is postulated as a mnemonic-based disorder, but we lack markers or treatments targeting pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. We demonstrate that closed-loop SWRs triggered neuromodulation of the medial forebrain bundle (MFB) can enhance the consolidation of fear extinction. It modified fear memories that became resistant to induced recall (i.e., renewal and reinstatement) and did not reemerge spontaneously as a PTSD-like phenotype. The effects are mediated by D2 receptor signaling induced synaptic remodeling in the basolateral amygdala. These results suggest that SWRs help consolidating fear extinction memories. Furthermore, enhancing the consolidation of extinction engrams by SWR-triggered induction of reward signals can alleviate pathologic fear reactions in a rodent model of PSTD. No adverse effects were seen, suggesting this potential therapy for PTSD and anxiety disorders.