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

R.D. Webler, H. Berg, K. Fhong, L. Tuominen, D.J. Holt, R.A. Morey, I. Lange, P.C. Burton, M.A. Fullana, J. Radua, S. Lissek*

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review

9 Citations (Web of Science)

Abstract

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, striatalthalamic, 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.
Original languageEnglish
Pages (from-to)421-436
Number of pages16
JournalNeuroscience and Biobehavioral Reviews
Volume128
DOIs
Publication statusPublished - 1 Sep 2021

Keywords

  • Fear generalization
  • Fear conditioning
  • fMRI
  • Neuroimaging
  • Meta-analysis
  • ANTERIOR CINGULATE CORTEX
  • VENTROMEDIAL PREFRONTAL CORTEX
  • NORADRENERGIC LOCUS-COERULEUS
  • FACILITATES MEMORY RETRIEVAL
  • CONDITIONED FEAR
  • PATTERN SEPARATION
  • PERIAQUEDUCTAL GRAY
  • STIMULUS-GENERALIZATION
  • VENTRAL HIPPOCAMPUS
  • DORSAL HIPPOCAMPUS

Cite this