Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

Abstract

Background: Exposure-based therapies are used to treat a variety of trauma- and anxiety-related disorders by generating successful extinction following cue exposure during treatment. The development of adjuvant strategies that accelerate extinction learning, improve tolerability, and increase efficiency of treatment could increase the efficacy of exposure-based therapies. Vagus nerve stimulation (VNS) paired with exposure can enhance fear extinction, in rat models of psychiatric disorders, and chronic administration of VNS reduces anxiety in rats and humans. Objective: We tested whether VNS, like other cognitive enhancers, could produce generalization of extinction for stimuli that are not presented during the extinction sessions, but are associated with the fear event. Methods: Male Sprague Dawley rats underwent auditory fear conditioning with two easily discriminable auditory stimuli. Following fear conditioning, extinction training consisted of exposure to only one of the conditioned sounds. Half of the rats received VNS and half received sham stimulation during with sound presentations. VNS effects on anxiety were examined in a separate study where VNS was administered prior to testing on the elevated plus maze. Results: Sham stimulated rats given 20 presentations of a conditioned stimulus (CS) during the extinction session showed performance that was matched to VNS-treated rats given only 4 presentations of the CS. Despite comparable levels of freezing to the presented CS, only the VNS-treated rats showed a significant decrease in freezing to the CS that was not presented. VNS-induced generalization of extinction was observed only when the two sounds were paired with footshock within the same fear conditioning session; VNS did not promote generalization of extinction when the two sounds were conditioned on different days or in different contexts. On the anxiety test, VNS administration significantly increased time spent in the open arms of the elevated plus maze. Conclusion: These results provide evidence that VNS can promote generalization of extinction to other stimuli associated with a specific fear experience. Furthermore, non-contingent VNS appears to reduce anxiety. The ability to generalize extinction and reduce anxiety makes VNS a potential candidate for use as an adjunctive strategy to improve the efficacy and tolerability of exposure-based therapies.

Peripheral effects of vagus nerve stimulation on anxiety and extinction of conditioned fear in rats

“…Methyl-scop:VNS was not different from saline:sham or methyl-scop:sham and methyl-scop: sham was not different from saline:sham. Consistent with our previous study, VNS was sufficient to increase time spent in the open arms of the EPM in saline-treated rats (Noble et al 2019), but we did not observe this anxiolytic effect in methyl-scop-treated rats. There was not a significant interaction (F (1,32) = 0.08, P = 0.7758), drug (F (1,32) = 2.148, P = C B A Figure 1.…”

“…VNS may provide an added benefit of reducing anxiety during therapy. Chronic VNS reduces anxiety in rats (Furmaga et al 2011;Shah et al 2016) and in humans (George et al 2008), and we recently found that short-term administration of VNS increased the time that rats spent in the open arms of an elevated plus maze (EPM) (Noble et al 2019). The vagus nerve is part of the parasympathetic peripheral nervous system and it is called the "vagal brake" because it counteracts the sympathetic effects of stress on the heart and other organs.…”

Promoting long-term inhibition of human fear responses by non-invasive transcutaneous vagus nerve stimulation during extinction training

“…Accordingly, active tVNS significantly reduced cognitive risk assessments relative to sham stimulation, when a cue was no longer predicting an aversive event. As this effect was strongest early during extinction learning and was even evident right from the start of extinction training, we may assume rapid anxiolytic effects, as proposed by previous rodent research 41 . However, even more remarkable, although the initial spontaneous recovery of fear after a passage of 24 hours has not been prevented by a tVNS-paired extinction training, it in fact promoted flexible cognitive adaptation and further facilitated the extinction of cognitive risk assessments 24 hours later during a subsequent extinction test.…”

“…It has been repeatedly proposed that transcutaneous vagus nerve stimulation results in both anxiolytic effects and enhanced cognitive flexibility in humans and rodents [39][40][41][42] . In fact, our results support the hypothesis, that tVNS promotes both an overall reduction of cognitive risk assessments and a flexible cognitive adaptation to changing aspects of the environment.…”

Adversity History Predicts Self-Reported Autonomic Reactivity and Mental Health in US Residents During the COVID-19 Pandemic

“…Although there are many external influences on the ANS, the most direct evidence supporting a causal association between the ANS and mental health come from vagal nerve stimulation (VNS), which uses an electrical current to stimulate vagal afferent pathways that lead from the periphery to the brainstem. There is now substantial evidence that vagal nerve stimulation can improve depression symptoms (22,23) and modulate anxiety and fear (24,25), supporting a causal connection between autonomic signaling and emotional well-being.…”