The relationship between dlPFC activity during unpredictable threat and CO2-induced panic symptoms

Abstract

Panic disorder is characterized by sudden, repeated, and unexpected attacks of intense fear and overwhelming anxiety about when another attack may strike. Patients with panic disorder and healthy individuals with a history of panic attacks show a hypersensitivity to unpredictable threats, suggesting a possible link between panic and sustained anxiety. The purpose of this study was to determine the degree to which induced symptoms of panic relate to fear and anxiety, as well as activity in the neural systems that mediate and regulate these affective states. Psychological and physiological symptoms of panic were assessed during an 8-min 7.5% CO₂ challenge task. Psychological, physiological, and neural symptoms of fear and anxiety were measured during two sessions (one psychophysiology and one functional magnetic resonance imaging where subjects experienced several blocks of no threat (N), predictable shock (P), and unpredictable shock (U; NPU threat task). We used a principle component analysis to characterize panic susceptibility (PS), and found that PS significantly predicted dorsolateral prefrontal cortex (dlPFC) activity to the unpredictable cue during the NPU threat task. When examining the weighted beta coefficients from this analysis, we observed that self-reported fear/anxiety during the CO₂ challenge negatively loaded onto dlPFC activity during the NPU task. Consistent with this observation, dlPFC activity during the unpredictable cue was also negatively correlated with anxiety during the NPU sessions. Together, these results suggest that panic symptoms and anxiety are regulated by the same prefrontal cognitive control system.

Trial registration: ClinicalTrials.gov NCT00047853.

Fig. 1. Design and primary outcome measures from the 7.5% CO₂ challenge

a Schematic demonstrating timeline of the CO₂ challenge. During the pre-CO₂ and recovery periods, subjects breathe room air. During the CO₂ administration period, subjects breathe room air enriched with 7.5% CO₂. b–k Physical b–g and psychological h–l symptoms of CO₂ administration. Bars represent the mean CO₂ − Pre-CO₂ values ± SEM

Fig. 2. Design and behavioral outcome measures from the NPU sessions

a Schematic demonstrating design of the NPU paradigm. Colored lines indicate blocks of neutral, predictable, and unpredictable threat. Geometric shapes indicate visual cues presented during blocks. Lightning bolts represent timing of shock delivery. b Average anxiety ratings during the fMRI session for the neutral (N), predictable (P), and unpredictable (U) blocks when the cue was present (Cue) or absent (ITI) from the screen. c Startle magnitude (t-scores) during the laboratory session for the neutral (N), predictable (P), and unpredictable (U) blocks when the cue was present (Cue) or absent (ITI) from the screen. d Average anxiety ratings during the laboratory session for the neutral (N), predictable (P), and unpredictable (U) blocks when the cue was present (Cue) or absent (ITI) from the screen. Bars represent the mean ± SEM

Fig. 3. Main effects from the analysis of the BOLD data from the NPU fMRI session

a Statistical parametric map and corresponding graphic representation for regions of the fear network (FN). b Statistical parametric map and corresponding graphic representation for regions of the DMN. c Statistical parametric map and corresponding graphic representation for regions of the right dorsolateral prefrontal cortex (dlPFC). Bars represent the mean ± SEM

Fig. 4. Statistical relationship between measures from the CO₂ challenge and NPU sessions

a Screenplot demonstrating outcome of the principal components analyses for the CO₂ challenge. Components with an eigenvalue >1 are considered signal components, while those with an eigenvalue <1 are considered noise components. b Variability (r ²) in dependent measures from the NPU sessions accounted for by the signal components in the CO₂ challenge. Filled bars are significant after correcting for multiple comparisons. Hatched bars are trends, but not significant after correcting for multiple comparisons. c Weighted beta coefficients showing contributions of specific items from the CO₂ challenge to the PCA/regression model predicting anxiety-related dlPFC activity. d Correlation between anxiety-related dlPFC activity and anxiety (as derived via PCA from NPU startle and ratings during fMRI and laboratory sessions)