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

Ryan D Webler, Hannah E Berg, Kimberly Fhong, Lauri Tuominen, Daphne J. Holt, Rajendra A. Morey, Iris Lange, Philip C. Burton, Miquel Angel Fullana, Joaquim Radua, Shmuel Lissek

Research output: Contribution to journalReview articlepeer-review

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, 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.

Original languageEnglish (US)
Pages (from-to)421-436
Number of pages16
JournalNeuroscience and Biobehavioral Reviews
Volume128
DOIs
StatePublished - Sep 2021

Bibliographical note

Funding Information:
This work was supported by the National Institute of Health MH080130 [SL]; R01MH095904 [DH]; RO1NS086885 [RM]. Additional support came from the Sigrid Juselius Fellowship grant (Tuominen); the Veterans Health Affairs (VHA) Mid-Atlantic Mental Illness Research Education and Clinical Center (MIRECC) and the Office of Research and Development ( 5I01CX000748-01 , 5I01CX000120-02 ) [RM]; and S tichting the Weijerhorst [IL].

Funding Information:
This work was supported by the National Institute of HealthMH080130 [SL]; R01MH095904 [DH]; RO1NS086885 [RM]. Additional support came from the Sigrid Juselius Fellowship grant (Tuominen); the Veterans Health Affairs (VHA) Mid-Atlantic Mental Illness Research Education and Clinical Center (MIRECC) and the Office of Research and Development (5I01CX000748-01, 5I01CX000120-02) [RM]; and Stichting the Weijerhorst[IL].

Publisher Copyright:
© 2021 Elsevier Ltd

Keywords

  • Fear conditioning
  • Fear generalization
  • Meta-analysis
  • Neuroimaging
  • fMRI

PubMed: MeSH publication types

  • Journal Article
  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

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