Reorienting TMS treatments for fear memories and posttraumatic stress disorder. The emerging potential of the anterior prefrontal cortex

Abstract

Posttraumatic stress disorder (PTSD) is characterized by re-experiencing trauma through vivid and involuntary intrusions, avoidance of cues that could trigger traumatic memories, and alterations in mood and cognition. Transcranial magnetic stimulation (TMS) offers a promising approach to modulating activity and functional coupling within neural circuits underlying these processes. To date, TMS studies in fear-conditioning research and PTSD have mainly focused on dorsolateral prefrontal cortex (dlPFC) and ventromedial (vmPFC)-connected or broader medial-prefrontal (mPFC) targets, yielding encouraging but heterogeneous effects on posttraumatic symptoms. In parallel, emerging evidence has implicated the anterior prefrontal cortex (aPFC; Brodmann area 10) in threat- and trauma-related processes, including memory retrieval, higher-order control of defensive responding, adaptive strategy selection, and resilience. Whereas the dlPFC and vmPFC have been incorporated into mechanistic models of fear regulation, the aPFC has received limited attention in theoretical frameworks of fear and PTSD. Here, we review TMS studies organized around dlPFC, vmPFC-connected or mPFC, and aPFC neuroanatomical targets, integrating evidence from experimental and clinical research. Based on the hierarchical model of prefrontal organization, we argue that these regions represent potential TMS targets or circuit nodes, but likely act on partially distinct mechanisms. The vmPFC appears primarily involved in early automatic downregulation of defensive responses; the dlPFC may support cognitive control strategies such as reappraisal; and the aPFC may enable a supraordinate influence over higher-order representations and avoidance-related circuitry, as well as flexible selection of emotion-regulation strategies. We conclude that integrating the aPFC into this framework may guide next-generation, mechanistically-informed TMS treatments for PTSD.