Poor between-session recall of extinction learning and hippocampal activation and connectivity in children

Abstract

Background: In healthy adults, successful between-session recall of extinction learning depends on the hippocampus and ventromedial prefrontal cortex (vmPFC), especially when tested in the extinction context. Poor extinction recall and dysfunction within hippocampal-vmPFC circuitry are associated with fear-based disorders (e.g., anxiety, posttraumatic stress disorder). Despite the early age of onset of virtually all fear-based disorders and the protracted development of the hippocampus and vmPFC across the first two decades of life, little is known about extinction recall and the underlying neural correlates in children.

Methods: Here, we tested extinction recall in 43 pre-adolescent children (ages 6-11 yrs) by coupling functional magnetic resonance imaging and virtual reality with a novel interpersonal threat-related two-day (ABBA) fear-extinction paradigm. Conditioned fear responding was assessed at behavioral, subjective, physiological, and neural levels.

Results: Although children demonstrated intact within-session extinction, there was poor between-session recall of extinction learning (retention index: 13.56%), evidenced by elevations in skin conductance, avoidant behavioral responses, and subjective ratings. Elevations in conditioning fear responding were accompanied by activation in the hippocampus and insula, and increased connectivity of the hippocampus with the insula and dorsal anterior cingulate cortex - regions implicated in the return of fear in adult studies. Children who kept more distance from the extinguished cue during extinction subsequently demonstrated heightened hippocampal-cingulate coupling during recall, suggesting that avoidant behavior interferes with extinction retention.

Conclusions: Poor extinction recall in children may have implications for developmental vulnerability to fear-based disorders, and for the application of therapeutic strategies that rely on principles of extinction (e.g., exposure therapy) to pediatric samples.

Keywords: Anterior cingulate cortex; Context; Extinction retention; Fear learning; Insula; fMRI.

Figure 1.. Schematic of experimental protocol.

Day one consisted of fear conditioning and extinction learning in separate virtual reality (VR) environmental contexts, separated by a 10-minute delay. 24 hours later, participants completed a test of extinction recall in the extinction context, while undergoing functional magnetic resonance imaging (fMRI) scanning. Renewal of fear was subsequently tested in the conditioning context, on a laptop with headphones. A subset of participants (n = 9) completed all four sessions in VR, to examine the potential effect of the fMRI scan environment on extinction recall.

Figure 2.. Children show intact within-session extinction learning, but poor between-session extinction recall.

Children show within-session extinction learning, evidenced by significant reductions in SCRs and fear ratings to the CS+E from fear conditioning to the end of extinction learning. Children show poor between-session recall, evidenced by elevations in SCRs and fear ratings to the CS+E from the end of extinction learning to the beginning of extinction recall. Extinction recall was tested in the extinction context (CXT-) 24 hours after fear conditioning and extinction learning sessions. Of note, fear ratings are on a scale from 1–5 where 1 = low fear and 5 = high fear. Similar results were obtained for US-expectancy ratings (see text). Abbreviations: SCRs, skin conductance responses; CXT-, extinction context; CXT+, fear conditioning context; CS+E, extinguished conditioned stimulus; CS+U, unextinguished conditioned stimulus; CS-, safety conditioned stimulus (unpaired with the US); US, unconditioned stimulus. Error bars represent standard error of the mean.

Figure 3.. Functional neural activation in the hippocampus and insula during a test of extinction recall in children, tested ~24 hours after extinction learning.

Results significant using small-volume family-wise error correction (pFWE < 0.05), within anatomically defined regions of interest (Tzourio-Mazoyer et al., 2002). No masking was applied to images. Displayed at p < 0.005, >5 voxels. Abbreviation: CS+E, previously extinguished cue; FWE, familywise error corrected.

Figure 4.. Positive hippocampal coupling with the dACC and insula during a test of extinction recall in children, tested ~24 hours following extinction learning.

Task-based functional connectivity was estimated using a gPPI analysis, by creating a 6-mm radius sphere around the group peak of activation for CS+E (see Figure 3). Similar results were obtained using a right hippocampal seed (see text). Results significant using small-volume family-wise error correction (pFWE < 0.05), within anatomically defined regions of interest (Tzourio-Mazoyer et al., 2002). No masking was applied to images. Abbreviations: dACC, dorsal anterior cingulate cortex; CS+E, previously extinguished cue; gPPI, generalized psychophysiological interaction; FWE, familywise error corrected.

Figure 5.. Children who kept more distance from the CS+E during extinction showed higher hippocampal-dACC coupling during a test of extinction recall, performed 24 hours later.

Task-based functional connectivity was estimated using a gPPI analysis, by creating a 6-mm radius sphere around the group peak of activation in the hippocampus for CS+E (see Figure 3). Significant hippocampal-dACC connectivity was detected for the CS+E during extinction recall across the sample (see Figure 4). Bivariate correlations conducted by comparing virtual distance with individual-participant hippocampal-dACC connectivity values, from the group peak shown in Figure 4. Abbreviations: dACC, dorsal anterior cingulate cortex; gPPI, generalized psychophysiological interaction.