Mapping memory at scale: systems-level insights with translational and transdiagnostic relevance to fear-related disorders

Fear-related disorders—including post-traumatic stress disorder (PTSD), specific phobias, and generalized anxiety disorder—are among the most prevalent and treatment-resistant psychiatric conditions. Despite decades of molecular and cellular advances, systemic pharmacological interventions and approaches targeting isolated brain regions have had limited therapeutic capacity, particularly in refractory patients. This mini-review argues that the translational impasse stems from a reductionist framework that treats mental disorders in general, and fear-related disorders in particular, as a localized phenomenon rather than a distributed network property. We synthesize recent evidence from engram research, oscillatory dynamics, and systems consolidation demonstrating that fear memories are encoded, maintained, and retrieved through brain-wide networks. We outline how emerging technologies such as high-density electrophysiology, calcium imaging, and functional neuroimaging combined with graph-theoretical analysis can map memory networks at scale, enabling precision interventions such as closed-loop neuromodulation and connectivity-based treatment prediction. Adopting a transdiagnostic perspective aligned with the Research Domain Criteria (RDoC), we position persistent aversive memory as a dimensional mechanism that crosses diagnostic boundaries, a perspective we propose as necessary for the development of more effective clinical interventions.