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.
Highlights
Recognizing threat and responding appropriately to danger is essential for survival of an organism
Studies in experimental animals have documented that activation of vagal afferents, which during an emotional experience may be elicited by peripheral adrenalin binding to vagal β-adrenergic receptors[28], mediates the release of norepinephrine (NE) in key structures of emotional memory formation including the amygdala, hippocampus and ventromedial prefrontal cortex[29,30], either directly via the nucleus tractus solitarius (NTS) or indirectly via the locus coeruleus (LC)[31,32]
The auricular branch of the vagus nerve (ABVN) has the same ratio of afferent myelinated A beta axons as the cervical vagus nerve (CVN), which indicates similar effects of transcutaneous vagus nerve stimulation via the ear[39]
Summary
Recognizing threat and responding appropriately to danger is essential for survival of an organism. In this single cue conditioning experiment, they demonstrated faster extinction and less return of conditioned freezing in rats which received vagus nerve stimulation via implanted electrodes during extinction compared to a sham stimulated group. Burger et al.[42] investigated the effects of tVNS compared to Sham stimulation in healthy humans using a classical cue conditioning paradigm with geometric shapes They found accelerated fear extinction in US expectancy ratings. A study in humans investigating the effects of tVNS on the extinction of contextual anxiety and relapse is still missing For this investigation, we modified the context conditioning paradigm in virtual reality used in Glotzbach-Schoon et al.[22] in order to fit it with the stimulation requirements and reinstatement parameters. This set up presents the advantage that participants can see their own body which increases feelings of presence (see Methods section)
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