Effect of Threat on Right dlPFC Activity during Behavioral Pattern Separation

Abstract

It has long been established that individuals with anxiety disorders tend to overgeneralize attributes of fearful stimuli to nonfearful stimuli, but there is little mechanistic understanding of the neural system that supports overgeneralization. To address this gap in our knowledge, this study examined effect of experimentally induced anxiety in humans on generalization using the behavioral pattern separation (BPS) paradigm. Healthy subjects of both sexes encoded and retrieved novel objects during periods of safety and threat of unpredictable shocks while we recorded brain activity with fMRI. During retrieval, subjects were instructed to differentiate among new, old, and altered images. We hypothesized that the hippocampus and dorsolateral prefrontal cortex (dlPFC) would play a key role in the effect of anxiety on BPS. The dlPFC, but not the hippocampus, showed increased activity for altered images compared with old images when retrieval occurred during periods of threat compared with safety. In addition, accuracy for altered items retrieved during threat was correlated with dlPFC activity. Together, these results suggest that overgeneralization in anxiety patients may be mediated by an inability to recruit the dlPFC, which mediates the cognitive control needed to overcome anxiety and differentiate between old and altered items during periods of threat.SIGNIFICANCE STATEMENT Anxiety and posttraumatic stress disorder patients generalize fear to nonfearful fear stimuli, making it difficult to regulate anxiety. Understanding how anxiety affects generalization is key to understanding the overgeneralization experienced by these patients. We examined this relationship in healthy subjects by studying how threat of shock affects neural responses to previously encountered stimuli. Although previous studies point to hippocampal involvement, we found that threat affected activity in the dorsolateral prefrontal cortex (dlPFC), rather than the hippocampus, when subjects encountered slightly altered versions of the previously encountered items. Importantly, this dlPFC activity predicted performance for these items. Together, these results suggest that the dlPFC is important for discrimination during elevated anxiety and that overgeneralization may reflect a deficit in dlPFC-mediated cognitive control.

Trial registration: ClinicalTrials.gov NCT00047853.

Keywords: anxiety; dlPFC; fMRI; pattern separation; threat of shock.

Copyright © 2017 the authors 0270-6474/17/379160-12$15.00/0.

Figures

Figure 1.

Schematic of experimental design. A, Subjects viewed novel items during blocks of threat and safety. B, Subjects viewed new, old, and altered items during blocks of threat and safety. New items were those that had not been presented during the encoding phase. Old items were those presented in the same orientation as in the encoding phase. Altered items were rotated slightly compared with when they were presented during encoding. Half of the repeated items (old and altered) were encoded during threat and the other half were encoded during safety. Lightning bolts represent the unpredictable shocks presented in the threat periods.

Figure 2.

Performance during the retrieval phase. A, Accuracy for old and altered items during retrieval. B, Reaction time for items presented during retrieval. Error bars indicate mean ± SEM.

Figure 3.

Whole-brain BOLD effects of threat and item type for the encoding and retrieval phases. A, Effect of threat on BOLD responses to items during the encoding phase. B, Effect of threat on BOLD responses to items during the encoding phase. C, Effect of item type on BOLD responses during the retrieval phase.

Figure 4.

Effect of threat during retrieval and item type on BOLD responses in the dLPFC. Error bars indicate mean ± SEM.

Figure 5.

BOLD responses to correct and incorrect items during retrieval in the dlPFC. ROI represents the dlPFC cluster from the main analysis in Figure 4. Error bars indicate mean ± SEM.

Figure 6.

Scatter plots examining correlations between accuracy and dlPFC activity during the retrieval phase. A, Correlations for old and altered items presented during periods of safety during retrieval. B, Correlations for old and altered items presented during periods of threat during retrieval.

Figure 7.

Correlations between accuracy and dlPFC activity during retrieval for correctly and incorrectly identified old (A, B) and altered (C, D) items during the safe (B, D) and threat (B, D) conditions. Black squares and items represent correct items and red squares and lines represent incorrect items.

Figure 8.

BOLD responses to old and altered items during retrieval in the CA3 region of the hippocampus. A, ROIs represent the extent of the CA3 region (orange) in an example subject. B, Percent signal change in CA3 evoked by Old and Altered items. Error bars indicate mean ± SEM.

Figure 9.

BOLD responses to correct and incorrect altered items during retrieval in the CA3 (B), dentate gyrus (C), and CA1 (D). A, ROIs represent the extent of each subregion in an example subject. B–D, Bars represent percent signal change evoked by correct and incorrect trials. Error bars indicate mean ± SEM.