Unstable prefrontal response to emotional conflict and activation of lower limbic structures and brainstem in remitted panic disorder

Abstract

Background: The neural mechanisms of panic disorder (PD) are only incompletely understood. Higher sensitivity of patients to unspecific fear cues and similarities to conditioned fear suggest involvement of lower limbic and brainstem structures. We investigated if emotion perception is altered in remitted PD as a trait feature.

Methodology/principal findings: We used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to study neural and behavioural responses of 18 remitted PD patients and 18 healthy subjects to the emotional conflict paradigm that is based on the presentation of emotionally congruent and incongruent face/word pairs. We observed that patients showed stronger behavioural interference and lower adaptation to interference conflict. Overall performance in patients was slower but not less accurate. In the context of preceding congruence, stronger dorsal anterior cingulate cortex (dACC) activation during conflict detection was found in patients. In the context of preceding incongruence, controls expanded dACC activity and succeeded in reducing behavioural interference. In contrast, patients demonstrated a dropout of dACC and dorsomedial prefrontal cortex (dmPFC) recruitment but activation of the lower limbic areas (including right amygdala) and brainstem.

Conclusions/significance: This study provides evidence that stimulus order in the presentation of emotional stimuli has a markedly larger influence on the brain's response in remitted PD than in controls, leading to abnormal responses of the dACC/dmPFC and lower limbic structures (including the amygdala) and brainstem. Processing of non-panic related emotional stimuli is disturbed in PD patients despite clinical remission.

Figure 1. Emotional conflict paradigm.

(A) Basic stimulus material consisting of congruent and incongruent face expression/word pairs from eight subjects of the Ekman faces collection (fearful and happy face expression; words ‘happy’ and ‘fear’). (B) Categorization of trials into four order types (cC, iC, cI, iI) depending on congruence of the previous and the current trial. (C) Each 38 randomized stimuli were presented in four blocks (see methods section) with jittered interstimulus interval. The second trial in the depicted example would be classified as ‘cI’, and the third trial as ‘iI’, also referred to as low and high conflict resolution trials .

Figure 2. Conflict adaptation effects in controls and patients

. Note generally slower RTs in patients. Labels on x-axes refer to the current trial. (A) For reaction times a significant previous×congruence interaction was found for both groups (controls: F = 13.760, p = 0.0002; patients: F = 8.104, p = 0.0045). (B) For accuracy rates an effect of congruence of the current trial (controls: F = 14.280, p = 0.003; patients: F = 7.328, p = 0.085) was found, but no effect of previous trial type or the previous×congruence interaction.

Figure 3. fMRI response to conflict in general and to conflict depending on the type of preceding trial as analyzed in the separate groups.

(A) Significant clusters of activation and deactivation to incongruent vs. congruent trials (I>C) in controls (see supplemental data for result tabulation). (B) Control subjects showing stronger ventral ACC activation in conflict trials preceded by incongruent trials (Stroop_INC>Stroop_CON). (C) Contrary, patients showed more activation with preceding congruence in dACC/dmPFC (Stroop_CON>Stroop_INC) and further regions detailed in table 2. (D) In response to conflict trials preceded by incongruent trials, patients exhibited bilateral temporomesial including right amygdala, and brainstem activation (table 2).

Figure 4. Across group comparison of response to conflict as separated by preceding trial type

. (A) In response to conflict trials preceded by congruent trials (Stroop_CON) patients showed stronger dACC/dmPFC activation than controls. This effect was based on activation in patients and deactivation in controls (contrast estimates extracted at peak voxel x = 2, y = 30, z = 22, cluster thresholded at p_voxel<0.005). (B) In response to conflict trials preceded by incongruent trials (Stroop_INC) patients showed stronger right temporomesial including amygdalar activation. Extraction of contrast estimates (peak voxel within amygdala mask, x = 18, y = −8, z = −20) demonstrated that activation occured only in patients, showing a positive correlation with their behavioural interference (rho = 0.461, p = 0.013). (C) Isolation of the effect of the previous trial type revealed less dmPFC/ACC activation in patients compared with controls when switching from incongruent to congruent background. (D) In turn, patients showed more activation of the bilateral amygdala-hippocampal complex and the brainstem. The inlay shows the most robust part of the cluster locating to the upper pons and midbrain area (p_voxel<0.01, corrected p_cluster = 0.034).