Transcranial Direct Current Stimulation of the Ventromedial Prefrontal Cortex Modulates Perceptual and Neural Patterns of Fear Generalization

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 hyporeactivity to safety-signaling stimuli. We aimed to examine whether behavioral and neural patterns of fear generalization are influenced by the fear-inhibiting ventromedial prefrontal cortex (vmPFC). Three groups of healthy participants received excitatory (n = 27), inhibitory (n = 26), or sham (n = 26) transcranial direct current stimulation of the vmPFC after a fear conditioning phase and before a fear generalization phase. We obtained, as dependent variables, fear ratings and unconditioned stimulus–expectancy ratings, perceptual aspects of fear generalization (perceptual discrimination), pupil dilations, and source estimations of event-related fields elicited by conditioned and generalization stimuli. After inhibitory (compared with excitatory and sham) vmPFC stimulation, we observed reduced performance in perceptual discrimination and less negative inhibitory gradients in frontal structures at midlatency and late time intervals. Fear and unconditioned stimulus–expectancy ratings as well as pupil dilation remained unaffected by stimulation. These findings reveal a causal contribution of vmPFC reactivity to generalization patterns and suggest that vmPFC hyporeactivity consequent on 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.