Cortico-Striatal Activity Characterizes Human Safety Learning via Pavlovian Conditioned Inhibition

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and secu-rity-seeking behaviors. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (7 Tesla) fMRI to examine the neural basis of safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat omission when paired with a known threat signal (A1/AX-), and a standard safety signal that generally predicted threat omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation (PFDR whole-brain corrected). The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular, and dorsolateral PFC compared with the standard safety signal, whereas the latter evoked greater activation of the ventromedial PFC, posterior cingulate, and hippocampus, among other regions. Further analy-ses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, mid-brain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS???). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of ???stimulus??? safety??? associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.