Transcranial direct current stimulation of the ventromedial prefrontal cortex modulates perceptual and neural patterns of fear generalization

Abstract Background Overgeneralization of fear is a pathogenic marker of anxiety and stress-related disorders and has been linked with perceptual discrimination deficits, reduced fear inhibition, and prefrontal hypo-reactivity to safety signaling stimuli. Objective We aimed to examine whether behavioral and neural patterns of fear generalization are influenced by the “fear-inhibiting” ventromedial prefrontal cortex (vmPFC). Methods Three groups of healthy participants received excitatory (N=27), inhibitory (N=26) or sham (N=26) transcranial direct current stimulation (tDCS) of the vmPFC after a fear conditioning and before a fear generalization phase. As dependent variables, we obtained fear ratings and UCS-expectancy ratings, perceptual aspects of fear generalization (perceptual discrimination), pupil dilations and source estimations of event-related fields elicited by conditioned and generalization stimuli (CS, GS). Results After inhibitory (compared to excitatory and sham) vmPFC stimulation, we observed reduced performance in perceptual discrimination and less negative “inhibitory” gradients in frontal structures at mid-latency and late time intervals. Fear and UCS-expectancy ratings as well as pupil dilation remained unaffected by stimulation. Conclusions These findings reveal a causal contribution of vmPFC reactivity to generalization patterns and suggest that vmPFC hypo-reactivity consequent upon inhibitory vmPFC stimulation may serve as a model for pathological processes of fear generalization (reduced discrimination, impaired fear inhibition via frontal brain structures). This encourages further basic and clinical research on the potential of targeted brain stimulation to modulate fear generalization and overgeneralization.