Comparison of behavioral and brain indices of fear renewal during a standard vs. novel immersive reality Pavlovian fear extinction paradigm in healthy adults

Abstract

Pavlovian conditioning paradigms model the learned fear associations inherent in posttraumatic stress disorder, including the renewal of inappropriate fear responses following extinction learning. However, very few studies in humans investigate the underlying neural mechanisms involved in fear renewal despite its clinical importance. To address this issue, our lab designed a novel, immersive-reality Pavlovian fear acquisition, extinction, recall, and renewal paradigm. We utilized an ecological threat - a snake striking towards the participant - as the unconditioned stimulus (US). Context and background were dynamic and included both visual and auditory cues that are relevant to everyday life. Using functional magnetic resonance imaging and behavioral measures (US expectancy ratings), we examined the validity of this Novel paradigm in healthy adults (n = 49) and compared it to a Standard, well-validated 2D paradigm (n = 28). The Novel paradigm, compared to the Standard, was associated with greater hippocampal activation throughout the task. Participants who underwent the Standard paradigm, compared to the Novel, also displayed insula activation; however, this was not specific to stimulus or time. During fear renewal, the Novel paradigm was associated with dorsal anterior cingulate cortex activation to CS+ (> CS-). Overall, we found that our Novel, immersive-reality paradigm, which features an ecologically relevant US, elicited greater corticolimbic activation. These results suggest that immersive Pavlovian fear conditioning paradigms paired with innately fearful stimuli may improve translatability of preclinical paradigms to clinical interventions for fear-based disorders.

Keywords: Amygdala; FMRI; Fear renewal; Hippocampus; Prefrontal cortex; Virtual reality.

Fig. 1.. Standard and Novel paradigms.

(a) The Standard paradigm has a 4 second CS period (light post illuminated), where during reinforced trials the US co-terminates for the last 0.5 seconds of the trial (noise burst). During the Novel paradigm, the CS (messenger bag) period is 4.5 seconds with a US co-termination of 0.8 seconds (snake striking and hissing). (b) The Standard paradigm occurs over three days, with slightly longer phase times compared to the (c) Novel paradigm that occurs over two days. Icon images were sourced from Flaticon.com using the following search terms: ‘computer screen’, ‘MRI’, ‘street lamp’, ‘noise’, ‘messenger bag’, and ‘snake’.

Fig. 2.. US expectancy ratings during each phase of Pavlovian conditioning within both paradigms.

Y-axis indicates percentage of responses for a given category. The dashed horizontal line indicates chance and * denotes a significant divergence from chance within each paradigm at Bonferroni-corrected p < 0.05. Fear conditioning is shown in panel (a), fear extinction learning in panel (b), extinction recall in panel (c), and fear renewal in panel (d). First column displays responses in the Standard paradigm, while the second column displays the Novel paradigm.

Fig. 3.. BOLD fMRI activation during fear extinction learning showing an interaction effect of paradigm x stimulus x time in the hippocampus.

Participants who underwent the Novel (vs. Standard) paradigm exhibited greater hippocampus activation to early (a) CS− and (b) CS+E > CS− (vs. late). Results significant at pFWE < 0.05; panel (a) shown at p < 0.05 and (b) shown at p < 0.005 for display purposes only. Contrast maps generated from significant t-tests reported in text using the ROI as an inclusive mask. Values on graph represent extracted 6 mm sphere from peak coordinate; error bars represent +/− 1 standard error of the mean.

Fig. 4.. BOLD fMRI activation during fear renewal showing an interaction effect of paradigm x stimulus in the dACC.

Participants who underwent the Novel (vs. Standard) paradigm exhibited greater dACC activation to the CS+ (> CS−). Results significant at pFWE < 0.05; image shown at p < 0.005. Contrast map generated from significant t-test reported in text using the ROI as an inclusive mask. Values on graph represent extracted 6 mm sphere from peak coordinate; error bars represent +/− 1 standard error of the mean.