Effects of Noradrenergic Stimulation Upon Context-Related Extinction Learning Performance and BOLD Activation in Hippocampus and Prefrontal Cortex Differ Between Participants Showing and Not Showing Renewal

Abstract

While the neural structures mediating context-related renewal of extinction are well established, the neurotransmitter systems processing renewal remain elusive. Noradrenergic stimulation before extinction improved learning, but did not alter renewal. Since context processing already during initial conditioning can influence renewal, in this fMRI study we investigated how noradrenergic stimulation by a single dose of atomoxetine (ATO) before initial acquisition of a context-related predictive-learning task affects subsequent learning and renewal in humans. ATO participants showing contextual renewal (REN) exhibited a selective extinction learning deficit compared to placebo (PLAC) and ATO participants lacking renewal (ATO NoREN), probably owing to formation of more stable associations during acquisition. New learning and retrieval during the extinction phase as well as initial acquisition were unimpaired. In ATO REN, higher activation in right inferior frontal gyrus (iFG) during acquisition may have supported the formation of more stable associations, while reduced activation in hippocampus and left iFG during extinction was associated with impaired context encoding and response inhibition. During recall, ATO REN showed reduced overall context-dependent renewal associated with higher activation in medial PFC and right hippocampus. The results demonstrate the importance of noradrenergic processing in inferior frontal cortex and hippocampus for human extinction learning, but not necessarily initial conditioning. Since an identical atomoxetine treatment evoked diverging blood-oxygen level dependent (BOLD) activation patterns in REN and NoREN participants, the effect is presumably related to the participants’ preferred processing strategies that may have recruited differentially interconnected networks in which noradrenergic stimulation produced diverging consequences. In the ATO REN group, probably an additive effect of their preferred processing strategy, which pre-activated the noradrenergic system, and the experimental treatment caused a shift beyond the optimal working range of the noradrenergic system, thus modulating BOLD activation in a way that impaired extinction learning and recall.

Effects of transcutaneous auricular vagus nerve stimulation on reversal learning, tonic pupil size, salivary alpha‐amylase, and cortisol

“…These unexpected results question whether and via what mechanism taVNS modulates the ability to learn changes in contingencies. In particular, the null effect of taVNS on reversal learning is in contradiction with previous studies showing a facilitating effect of atomoxetine in a similar predictive learning task (Lissek et al, 2015(Lissek et al, , 2019. The hypothesized noradrenergic mechanism cannot explain the observed difference in performance for the reversal relative to the distractor stimuli between the groups.…”

“…Such complexity may reduce the risk of ceiling effects at the beginning of the learning curve when the effect of taVNS can be expected to be maximal (Burger et al, 2016(Burger et al, , 2017Szeska et al, 2020). Lissek and colleagues developed a predictive learning task in which atomoxetine, a selective NA reuptake inhibitor, facilitated reversal learning in healthy humans (Lissek et al, 2015(Lissek et al, , 2019. Reversal learning can be conceptualized as a more complicated form of extinction learning (Goarin et al, 2018;Schiller & Delgado, 2010).…”

Left Inferior Frontal Gyrus Participates in Mediating the Renewal Effect Irrespective of Context Salience

“…The present results expand the findings from previous studies that too found-mainly incidental-iFG activation during extinction and recall (Lissek et al, 2015b;Klass et al, 2017;Lissek et al, 2019), by demonstrating for the first time differential activation of this region within the same individuals, depending on their momentary propensity to show renewal. This within-subject confirmation of previous between-subjects results highlights the important role iFG apparently has for processing renewal-related information.…”

“…Another prefrontal region potentially important for renewal is inferior frontal gyrus (iFG)-an area which in our previous studies was occasionally found activated during extinction learning and recall (e.g., Lissek et al, 2017Lissek et al, , 2019, and whose involvement in renewal is as yet unexplored. IFG is assumed to mediate response inhibition (Konishi et al, 1999), necessary during operant/instrumental extinction learning (Bouton et al, 2016).…”

Dopaminergic D2-like receptor stimulation affects attention on contextual information and modulates BOLD activation of extinction-related brain areas

“…The predictive learning task used in this study is a modified version of a learning task that was designed to reliably evoke a renewal effect in context-related extinction learning without a fear component 30 . Previous studies already used this task in a different version adapted for fMRI experiments 4 , 5 , 19 , 32 , 39 . Participants were asked to put themselves in the position of a physician and predict whether various food items (fruit or vegetable) served in two different restaurants would lead to the aversive consequence of a stomachache in their patient.…”