The neural basis of avoidance learning and its relation to safety processing.

Persistent avoidance plays a major role in maintaining anxiety disorders. The few studies that have explored the neural basis of avoidance have predominantly examined established avoidance behaviours rather than the learning processes that establish avoidance responses. We aimed to characterise the temporal dynamics and neural mechanisms of avoidance learning using a novel paradigm combined with 7-Tesla functional magnetic resonance imaging (fMRI) in 82 healthy participants (37 male and 45 female). Participants were first conditioned to two threat stimuli and a compound safety stimulus. Next, they were trained to avoid one threat stimulus while the other remained unavoidable. Behavioural data confirmed accurate learning of task contingencies. Successful avoidance was associated with prominent activation of the ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), and ventrolateral prefrontal cortex compared to unsuccessful avoidance, with additional nucleus accumbens and orbitofrontal cortex engagement when compared to safety learning (P FDR whole-brain corrected). Critically, early compared to late avoidance learning was distinctly associated with activation of midbrain-striatal circuits, including the periaqueductal grey (PAG), mediodorsal thalamus, substantia nigra, and anterior insular cortex-regions associated with threat processing and learning-related signalling. These findings suggest that initial avoidance learning relies on subcortical threat-responsive and learning-related circuits whereas established avoidance responses engage cortical safety-processing regions. This dissociation parallels recent findings in safety learning and provides novel mechanistic insights for interventions targeting maladaptive avoidance patterns.Significance statement Avoidance behaviour is central to anxiety disorders, yet the neural mechanisms through which avoidance is learned remain poorly understood. Using 7-Tesla fMRI and a novel paradigm in 82 participants, we show that initial human avoidance learning engages midbrain-striatal circuits-including the periaqueductal grey, substantia nigra, and thalamus-while established avoidance relies on cortical safety-processing regions centred on the ventromedial prefrontal cortex. This temporal dissociation parallels recent findings in Pavlovian safety learning and identifies a potential mechanistic window during which maladaptive avoidance patterns may be most amenable to intervention.