TY - JOUR
T1 - The neurobiology of human fear generalization
T2 - meta-analysis and working neural model
AU - Webler, Ryan D.
AU - Berg, Hannah
AU - Fhong, Kimberly
AU - Tuominen, Lauri
AU - Holt, Daphne J.
AU - Morey, Rajendra A.
AU - Lange, Iris
AU - Burton, Philip C.
AU - Fullana, Miquel Angel
AU - Radua, Joaquim
AU - Lissek, Shmuel
N1 - Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - Fear conditioning
KW - Fear generalization
KW - Meta-analysis
KW - Neuroimaging
KW - fMRI
UR - http://www.scopus.com/inward/record.url?scp=85109446821&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85109446821&partnerID=8YFLogxK
U2 - 10.1016/j.neubiorev.2021.06.035
DO - 10.1016/j.neubiorev.2021.06.035
M3 - Review article
C2 - 34242718
AN - SCOPUS:85109446821
SN - 0149-7634
VL - 128
SP - 421
EP - 436
JO - Neuroscience and Biobehavioral Reviews
JF - Neuroscience and Biobehavioral Reviews
ER -