Reinstatement of contextual conditioned anxiety in virtual reality and the effects of transcutaneous vagus nerve stimulation in humans

Since exposure therapy for anxiety disorders incorporates extinction of contextual anxiety, relapses may be due to reinstatement processes. Animal research demonstrated more stable extinction memory and less anxiety relapse due to vagus nerve stimulation (VNS). We report a valid human three-day context conditioning, extinction and return of anxiety protocol, which we used to examine efects of transcutaneous VNS (tVNS). Seventy-fve healthy participants received electric stimuli (unconditioned stimuli, US) during acquisition (Day1) when guided through one virtual ofce (anxiety context, CTX+) but never in another (safety context, CTX−). During extinction (Day2), participants received tVNS, sham, or no stimulation and revisited both contexts without US delivery. On Day3, participants received three USs for reinstatement followed by a test phase. Successful acquisition, i.e. startle potentiation, lower valence, higher arousal, anxiety and contingency ratings in CTX+ versus CTX−, the disappearance of these efects during extinction, and successful reinstatement indicate validity of this paradigm. Interestingly, we found generalized reinstatement in startle responses and diferential reinstatement in valence ratings. Altogether, our protocol serves as valid conditioning paradigm. Reinstatement efects indicate diferent anxiety networks underlying physiological versus verbal responses. However, tVNS did neither afect extinction nor reinstatement, which asks for validation and improvement of the stimulation protocol.

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