Neural and multimodal signatures of Threat Learning, Generalization, and Return of Fear linked to Adverse Childhood Experiences

Adverse childhood experiences (ACEs) are well established and strong risk factors for mental health challenges later in life, but the underlying mechanisms remain largely unclear. Associative learning, which shapes emotional and cognitive responses to environmental cues, may play a critical role in this relationship. However, the neural underpinnings linking ACEs and ACE load to alterations in associative threat and safety learning remain poorly understood. In this multimodal fMRI study, 171 participants (97 with ACEs, 74 without ACEs) underwent a one-day fear conditioning paradigm, which included fear acquisition, generalization, extinction, and a return of fear test (ROF) after reinstatement. During fear acquisition, generalization and the ROF test, higher ACE load was associated with reduced discrimination between threat and safety cues, primarily driven by blunted responses to the threat cue across arousal ratings and central nodes of the fear network key brain regions (striatal regions and the vmPFC). During fear generalization, individuals with ACEs showed reduced activation in key brain regions to the CS+ (and GS+) but no differences in generalization gradients. In contrast, ACEs were neither related to expectancy ratings for nor aversiveness ratings for the unconditioned aversive event. These findings indicate a striking dissociation between cognitive and affective threat processing - putatively originating from a reduced transfer of US-related arousal to the CS+ as a mechanistic pathway through which ACEs become physiologically and neurobiologically embedded, thereby increasing the risk for mental health challenges.