The neurobiology of human fear generalization: meta-analysis and working neural model.

Journal Article (Journal Article;Review)

Fear generalization to stimuli resembling a conditioned danger-cue (CS+) is a fundamental dynamic of classical fear-conditioning. Despite the ubiquity of fear generalization in human experience and its known pathogenic contribution to clinical anxiety, neural investigations of human generalization have only recently begun. The present work provides the first meta-analysis of this growing literature to delineate brain substrates of conditioned fear-generalization and formulate a working neural model. Included studies (K = 6, N = 176) reported whole-brain fMRI results and applied generalization-gradient methodology to identify brain activations that gradually strengthen (positive generalization) or weaken (negative generalization) as presented stimuli increase in CS+ resemblance. Positive generalization was instantiated in cingulo-opercular, frontoparietal, striatal-thalamic, and midbrain regions (locus coeruleus, periaqueductal grey, ventral tegmental area), while negative generalization was implemented in default-mode network nodes (ventromedial prefrontal cortex, hippocampus, middle temporal gyrus, angular gyrus) and amygdala. Findings are integrated within an updated neural account of generalization centering on the hippocampus, its modulation by locus coeruleus and basolateral amygdala, and the excitation of threat- or safety-related loci by the hippocampus.

Full Text

Duke Authors

Cited Authors

  • Webler, RD; Berg, H; Fhong, K; Tuominen, L; Holt, DJ; Morey, RA; Lange, I; Burton, PC; Fullana, MA; Radua, J; Lissek, S

Published Date

  • September 2021

Published In

Volume / Issue

  • 128 /

Start / End Page

  • 421 - 436

PubMed ID

  • 34242718

Electronic International Standard Serial Number (EISSN)

  • 1873-7528

Digital Object Identifier (DOI)

  • 10.1016/j.neubiorev.2021.06.035


  • eng

Conference Location

  • United States