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

Abstract

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 effects of transcutaneous VNS (tVNS). Seventy-five healthy participants received electric stimuli (unconditioned stimuli, US) during acquisition (Day1) when guided through one virtual office (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 effects during extinction, and successful reinstatement indicate validity of this paradigm. Interestingly, we found generalized reinstatement in startle responses and differential reinstatement in valence ratings. Altogether, our protocol serves as valid conditioning paradigm. Reinstatement effects indicate different anxiety networks underlying physiological versus verbal responses. However, tVNS did neither affect extinction nor reinstatement, which asks for validation and improvement of the stimulation protocol.

Transcutaneous vagus nerve stimulation and extinction of prepared fear: A conceptual non-replication

“…The lack of effects of tVNS on declarative fear extinction learning was unexpected, as this seems to contradict findings from our previous studies 6 , 7 . There they are in line, however, with a recent study which found no effects of tVNS on contextual fear extinction in a virtual reality environment 26 . The current study was designed to be a more highly powered conceptual replication of our previous studies.…”

“…In this study, no effects of tVNS on physiological indices of fear extinction were found, possibly indicating that tVNS affects fear extinction primarily via hippocampal, declarative pathways. Finally, another study tested the effects of tVNS on contextual fear conditioning in a virtual reality environment ( N = 75, divided into a sham, tVNS, and no stimulation group) 26 . The study used a three day protocol.…”

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

“…Since the control group received US presentations that were explicitly unpaired with the CS, such procedure might also have resulted in increased contextual anxiety in this group, as the US occurred unpredictably during the ITI 45 . However, as tVNS resulted in stronger effects in the fear learning group, we may assume that the extinction enhancing effects of tVNS might be specific to the extinction of cued fear, and may not affect the extinction of contextual anxiety, thus supporting previous work by Genheimer and coworkers 46 .…”

Pupil dilation as an implicit measure of appetitive Pavlovian learning

“…All negative peak values were transformed to zero. We applied the following quality criteria: (a) all trials with a baseline shift ≥5 µV were rejected from further analysis (EBR, PAR); (b) peak startle magnitudes ≤5 µV in the window of analysis were converted to zero (EBR; Genheimer, Andreatta, Asan, & Pauli, ; Glotzbach‐Schoon, Andreatta, Mühlberger, & Pauli, ). Lastly, all data were t scored ( z scored × 10 + 50).…”