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Fear is an emotional state, characterized by the activation of a defense system that is designed to ensure the organism’s survival. This system enables a rapid recognition of threats and organizes defensive response patterns in order to adaptively cope with the threatening environment. Yet, to ensure its flexibility under changing environmental conditions, inhibitory pathways exist that modulate the activation of this defense system, if a previously threatening cue no longer predicts any harm – a memory-formatting process referred to as fear extinction, leading to a reduction of defensive responding. Fear extinction is presumed to at least partially underlie exposure treatment of anxiety disorders, which is why the facilitation of this learning process may promote such treatment’s efficacy. Animal models suggested, that the stimulation of the vagus nerve or the superior colliculus (SC) – a midbrain structure mediating visual attentional processing – target these inhibitory extinction pathways and, thus, facilitate fear extinction. However, as it is unclear whether similar mechanisms exist in humans, this thesis manuscript examined how non-invasive stimulation of these inhibitory pathways by transcutaneous vagus nerve stimulation (tVNS) or SC-recruiting visual attentional manipulation impact on human fear extinction.
To this end, we conducted three studies using multiple-day single-cue fear conditioning and extinction paradigms. First, we elaborated on fear that is established in these paradigms by examining defensive responding that is elicited by an innocuous conditioned stimulus, which has either been paired (fear learning group) with an aversive unconditioned stimulus (US; an electric shock) or was unpaired (control group; study 1). During the following extinction training, either tVNS vs. sham stimulation was applied (study 1, study 2) or participants were instructed, to either generate saccadic eye movements (strong SC activation) vs. smooth eye pursuits (low SC activation; study 3). During subsequent sessions, extinction consolidation as well as the short- and long-term extinction recall was tested (study 2, study 3).
Conditioned fear in the fear learning group was characterized by elevated cognitive risk assessments (US-expectancy ratings), as well as increased cardiac deceleration and startle reflex potentiation compared to controls. Cardiac deceleration was positively correlated to startle potentiation, but was decoupled from cognitive risk assessments (study 1). Initial, short- and long-term extinction of these defensive responses was facilitated by tVNS on all three response levels (cognitive, physiological, behavioral; study 1, study 2). In contrast, saccades facilitated initial extinction only for physiological and behavioral elements of the defensive response pattern, while extinction consolidation and recall was impaired by any eye movement manipulation (study 3) for physiological and behavioral indicators of defensive responding.
Taken together, the data of the experimental series suggest, that on a behavioral level, conditioned fear may best be conceived as attentive immobility – a defense strategy elicited by inevitable distal threats, that is uniformly expressed across species and is accompanied by cardiac deceleration and startle reflex potentiation. In addition, it was shown that such rather automatic defensive adaptations are independent from verbally expressed threat expectancies. As expected, tVNS impacted on fear extinction on both levels, strongly in line with the suggestion, that vagal stimulation activates cortical and subcortical neural pathways involved in extinction learning, consolidation and recall. TVNS may, thus, be a promising adjuvant for exposure treatment of mental disorders. In contrast, SC-recruiting visual attentional manipulation only affected subcortically mediated defensive responding, in line with rodent findings, indicating that the SC specifically inhibits subcortical parts of the neural defense system. However, as extinction recall was impaired by any type of visual attentional manipulation, this appeared to have functioned as a form of avoidance, initially attenuating fear but preventing extinction consolidation and, thus, impairing sustained fear reduction. Both non-invasive stimulation techniques may therefore increase initial defensive flexibility in the face of no-longer threat-signaling stimuli, but only tVNS may achieve long-term effects on multiple response levels.