The Neurobiology of Human Fear Generalization: Meta-Analysis and Working Neural Model

Abstract

Fear generalization to stimuli resembling a conditioned danger-cue (CS+) is a fundamentaldynamic of classical fear-conditioning. Despite the ubiquity of fear generalization in human experience and the known pathogenic contribution of over-generalization to clinical anxiety, neural investigations of human generalization have only recently begun. The present work provides the first meta-analysis of this growing human 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 instantiated in nodes of the default mode (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 excitation of threat- or safety-related loci by the hippocampus.