Reduced attenuation of neural activation during fear extinction learning in patients with anxiety disorders: a delayed fear extinction fMRI study

Clarifying the patterns of neural activation during fear extinction in anxiety disorders (ADs) is essential for advancing our understanding of inhibitory learning. However, the underlying mechanisms remain poorly characterized in large, heterogeneous cohorts of patients. Utilizing a delayed fear extinction fMRI paradigm, this study examined neural responses in 280 patients with ADs — comprising panic disorder, agoraphobia, panic disorder with agoraphobia, social anxiety disorder, and multiple specific phobias — compared to 103 healthy controls (HC). The attenuation of neural activation to conditioned fear (CS+) and safety (CS−) stimuli from early versus late extinction was compared between groups. Subjective ratings of US-expectancy, arousal, and valence were also collected. In a whole-brain voxelwise analysis, patients showed significantly reduced attenuation of neural activation across both CS+ and CS− relative to HC from early compared to late phases of extinction learning. This pattern was observed in a broad network, encompassing the insular cortex (IC) and bilateral supplementary motor area (SMA), among other regions. No interaction between group and stimulus type was observed. Region-of-interest analysis of the left anterior insular cortex confirmed that reduced attenuation in this region represents a robust neural signature of altered extinction learning in ADs. Furthermore, patients reported persistently higher fear expectancy and arousal than HC, consistent with sustained alterations in threat-related processing following extinction training. Together, these findings highlight altered extinction-related neural attenuation as a transdiagnostic feature of ADs, offering novel insights into the neural mechanisms underlying fear extinction.