Reduced attenuation of neural activation during fear extinction learning in patients with anxiety disorders: a delayed fear extinction fMRI study
Abstract
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.
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BibTeX
@article{qian2026reduced,
title = {{Reduced attenuation of neural activation during fear extinction learning in patients with anxiety disorders: a delayed fear extinction fMRI study}},
author = {Zirong Qian and Yunbo Yang and Jan Richter and Katharina Domschke and Katja Koelkebeck and Jürgen Deckert and Martin J. Herrmann and Jens Plag and Andreas Ströhle and Hans-Ulrich Wittchen and Andre Pittig and Alfons Hamm and Volker Arolt and Udo Dannlowski and Silvia Schneider and Jürgen Margraf and Winfried Rief and Ulrike Lueken and Tilo Kircher and Isabelle C. Ridderbusch and Benjamin Straube},
journal = {Translational Psychiatry},
year = {2026},
month = nov,
doi = {10.1038/s41398-026-04430-7},
url = {https://www.nature.com/articles/s41398-026-04430-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Reduced attenuation of neural activation during fear extinction learning in patients with anxiety disorders: a delayed fear extinction fMRI study
AU - Zirong Qian
AU - Yunbo Yang
AU - Jan Richter
AU - Katharina Domschke
AU - Katja Koelkebeck
AU - Jürgen Deckert
AU - Martin J. Herrmann
AU - Jens Plag
AU - Andreas Ströhle
AU - Hans-Ulrich Wittchen
AU - Andre Pittig
AU - Alfons Hamm
AU - Volker Arolt
AU - Udo Dannlowski
AU - Silvia Schneider
AU - Jürgen Margraf
AU - Winfried Rief
AU - Ulrike Lueken
AU - Tilo Kircher
AU - Isabelle C. Ridderbusch
AU - Benjamin Straube
PY - 2026
DA - 2026/11/07
JO - Translational Psychiatry
DO - 10.1038/s41398-026-04430-7
UR - https://www.nature.com/articles/s41398-026-04430-7
AB - 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.
SN - 2158-3188
ER -