inhibiting fear-related thoughts and defensive behaviors when they are no longer appropriate to the situation is a prerequisite for flexible and adaptive responding to changing environments. Such inhibition of defensive systems is mediated by ventromedial prefrontal cortex (vmpfc), limbic basolateral amygdala (BLA), and brain stem locus-coeruleus noradrenergic system (Lc-nAs). noninvasive, transcutaneous vagus nerve stimulation (tVnS) has shown to activate this circuit. Using a multiple-day single-cue fear conditioning and extinction paradigm, we investigated long-term effects of tVnS on inhibition of low-level amygdala modulated fear potentiated startle and cognitive risk assessments. We found that administration of tVnS during extinction training facilitated inhibition of fear potentiated startle responses and cognitive risk assessments, resulting in facilitated formation, consolidation and long-term recall of extinction memory, and prevention of the return of fear. these findings might indicate new ways to increase the efficacy of exposure-based treatments of anxiety disorders.

During fear conditioning, a cue (CS) signals an inevitable distal threat (US) and evokes a conditioned response that can be described as attentive immobility (freezing). The organism remains motionless and monitors the source of danger while startle responses are potentiated, indicating a state of defensive hypervigilance. Although in animals vagally mediated fear bradycardia is also reliably observed under such circumstances, results are mixed in human fear conditioning. Using a single-cue fear conditioning and extinction protocol, we tested cardiac reactivity and startle potentiation indexing low-level defensive strategies in a fear-conditioned (n = 40; paired presentations of CS and US) compared with a non-conditioned control group (n = 40; unpaired presentations of CS and US). Additionally, we assessed shock expectancy ratings on a trial-by-trial basis indexing declarative knowledge of the previous contingencies. Half of each group underwent extinction under sham or active transcutaneous vagus nerve stimulation (tVNS), serving as additional proof of concept. We found stronger cardiac deceleration during CS presentation in the fear learning relative to the control group. This learned fear bradycardia was positively correlated with conditioned startle potentiation but not with declarative knowledge of CS-US contingencies. TVNS abolished differences in heart rate changes between both groups and removed the significant correlation between late cardiac deceleration and startle potentiation in the fear learning group. Results suggest, fear-conditioned cues evoke attentive immobility in humans, characterized by cardiac deceleration and startle potentiation. Such defensive response pattern is elicited by cues predicting inevitable distal threat and resembles conditioned fear responses observed in rodents. K E Y W O R D Sattentive immobility (freezing), extinction, fear bradycardia, fear conditioning, startle potentiation, transcutaneous vagus nerve stimulationThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

No abstract

The ventromedial prefrontal cortex (vmPFC) mediates the inhibition of defensive responses upon encounters of cues, that had lost their attribute as a threat signal via previous extinction learning. Here, we investigated whether such fear extinction recall can be facilitated by anodal transcranial direct current stimulation (tDCS). Extinction recall was tested twenty-four hours after previously acquired fear was extinguished. Either anodal tDCS or sham stimulation targeting the vmPFC was applied during this test. After stimulation ceased, we examined return of fear after subjects had been re-exposed to aversive events. Fear was assessed by reports of threat expectancy and modulations of autonomic (skin conductance, heart rate) and protective reflex (startle potentiation) measures, the latter of which are mediated by subcortical defense circuits. While tDCS did not affect initial extinction recall, it abolished the return of startle potentiation and autonomic components of the fear response. Results suggest hierarchical multi-level vmPFC functions in human fear inhibition and indicate, that its stimulation might immunize against relapses into pathological subcortically mediated defensive activation.

No abstract