Safety learning in anxiety, Pavlovian conditioned inhibition and Covid concerns

Experimental studies of fear conditioning have identified the effectiveness of safety signals in inhibiting fear and maintaining fear-motivated behaviours. In fear conditioning procedures, the presence of safety signals means that the otherwise expected feared outcome will not now occur. Differences in the inhibitory learning processes needed to learn safety are being identified in various psychological and psychiatric conditions. However, despite early theoretical interest, the role of conditioned inhibitors as safety signals in anxiety has been under-investigated to date, in part because of the stringent test procedures required to confirm the demonstration of conditioned inhibition as such. Nonetheless, the theoretical implications of an inhibitory learning perspective continue to influence clinical practice. Moreover, our understanding of safety signals is of additional importance in the context of the increased health anxiety and safety behaviours generated by the Covid-19 pandemic.

Cortico-striatal activity characterizes human safety learning via Pavlovian conditioned inhibition

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviours. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (UHF) fMRI to examine the neural basis of inhibitory safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat-omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat-omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation. The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular and dorsolateral prefrontal cortex compared to the standard safety signal, whereas the latter evoked greater activation of the ventromedial prefrontal cortex, posterior cingulate and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS-). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of stimulus-safety associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.

Second-Order Conditioning in Humans

In contrast to the large body of work demonstrating second-order conditioning (SOC) in non-human animals, the evidence for SOC in humans is scant. In this review, I examine the existing literature and suggest theoretical and procedural explanations for why SOC has been so elusive in humans. In particular, I discuss potential interactions with conditioned inhibition, whether SOC is rational, and propose critical parameters needed to obtain the effect. I conclude that SOC is a real but difficult phenomenon to obtain in humans, and suggest directions for future research.

EXPRESS: Inhibitory causal structures in serial and simultaneous feature negative learning

We have previously reported that human participants trained with a simultaneous feature negative discrimination (intermixed A+ / AB- trials) show only modest transfer of inhibitory properties of the feature B to a separately trained excitor in a summation test (Lee & Lovibond, 2021). Self-reported causal structure suggested that many participants learned that the effect of the feature B was somewhat specific to the excitor it had been trained with (modulation), rather than learning that the feature prevented the outcome (prevention). This pattern is reminiscent of the distinction between negative occasion-setting and conditioned inhibition in the animal conditioning literature. However, in animals, occasion-setting is more commonly seen with a serial procedure in which the feature (B) precedes the training excitor (A). Accordingly, we ran three experiments to compare serial with simultaneous training in an allergist causal judgment task. Transfer in a summation test was stronger to a previously modulated test excitor compared to a simple excitor after both simultaneous and serial training. There was a numerical trend towards a larger effect in the serial group, but it failed to reach significance and the Bayes Factor indicated support for the null. Serial training had no differential effect on self-reported causal structure, and did not significantly reduce overall transfer. After both simultaneous and serial training, transfer was strongest in participants who reported a prevention structure, replicating and extending our previous results to a previously modulated excitor. These results suggest that serial feature negative training does not promote a qualitatively different inhibitory causal structure compared to simultaneous training in humans.

Second-Order Conditioning and Conditioned Inhibition in Different Moments of the Same Training: The Effect of A+ and AX− Trial Number

The feature negative discrimination (A+/AX−) can result in X gaining excitatory properties (second-order conditioning, SOC) or in X gaining inhibitory properties (conditioned inhibition, CI), a challenging finding for most current associative learning theories. Research on the variables that modulate which of these phenomena would occur is scarce but has clearly identified the trial number as an important variable. In the set of experiments presented here, the effect of trial number was assessed in a magazine training task with rats as a function of both the conditioning sessions and the number of A+ and AX− trials per session, holding constant the total number of trials per session. The results indicated that SOC is most likely to be found at the beginning of training when there are many A+ and few AX− trials, and CI (as assessed by a retardation test) is most likely to be found at the end of training when there are few A+ and many AX− trials. Both phenomena were also found at different moments of training when the number of A+ trials was equal to the number of AX− trials. These results cannot be predicted by acquisition-focused associative models but can be predicted by theories that distinguish between learning and performance.

The Neural Correlates of Cued Reward Omission

Compared to our understanding of positive prediction error signals occurring due to unexpected reward outcomes, less is known about the neural circuitry in humans that drives negative prediction errors during omission of expected rewards. While classical learning theories such as Rescorla–Wagner or temporal difference learning suggest that both types of prediction errors result from a simple subtraction, there has been recent evidence suggesting that different brain regions provide input to dopamine neurons which contributes to specific components of this prediction error computation. Here, we focus on the brain regions responding to negative prediction error signals, which has been well-established in animal studies to involve a distinct pathway through the lateral habenula. We examine the activity of this pathway in humans, using a conditioned inhibition paradigm with high-resolution functional MRI. First, participants learned to associate a sensory stimulus with reward delivery. Then, reward delivery was omitted whenever this stimulus was presented simultaneously with a different sensory stimulus, the conditioned inhibitor (CI). Both reward presentation and the reward-predictive cue activated midbrain dopamine regions, insula and orbitofrontal cortex. While we found significant activity at an uncorrected threshold for the CI in the habenula, consistent with our predictions, it did not survive correction for multiple comparisons and awaits further replication. Additionally, the pallidum and putamen regions of the basal ganglia showed modulations of activity for the inhibitor that did not survive the corrected threshold.