Aberrant anterior cingulate processing of anticipated threat as a mechanism for psychosis

Abstract

Stress and abnormal stress response are associated with schizophrenia spectrum disorder (SSD), but the brain mechanisms linking stress to symptomatology remain unclear. In this study, we used a stress-based functional neuroimaging task, reverse-translated from preclinical studies, to test the hypothesis that abnormal corticolimbic processing of stressful threat anticipation is associated with psychosis and affective symptoms in SSD. Participants underwent an MRI-compatible ankle-shock task (AST) in which the threat of mild electrical shock was anticipated. We compared functional brain activations during anticipatory threat periods from N = 18 participants with SSD (10 M/8F) to those from N = 12 community controls (9 M/3F). After family-wise error correction, only one region, the ventral anterior cingulate cortex (vACC), showed significantly reduced activation compared with controls. vACC activation significantly correlated with clinical symptoms measured by the Brief Psychiatric Rating Scale total score (r = 0.54) and the psychosis subscale (r = 0.71), and inversely correlated with trait depression measured by the Maryland Trait and State Depression scale (r=-0.48). Deficient activation in vACC under stress of anticipated threat may lead to aberrant interpretation of such threat, contributing to psychosis and mood symptoms in SSD. This experimental paradigm has translational potential and may identify circuitry-level mechanisms of stress-related mental illness, leading to more targeted treatment.

Keywords: Ankle-shock; Functional imaging; Neuroimaging; Schizophrenia; Stress.

Figure 1:

(A) Cluster activation during threat-safe comparison based on community control (CC) minus schizophrenia spectrum disorder (SSD) cases at MNI z+16. Activation shown represents t-level by voxel (red = t>3.8). Red indicates decreased peak activation of a 274-voxel cluster located in ventral ACC in SSD compared to CC. Inset with box-and-whisker plot showing group differences. (B) AST task-based vACC activation is associated with BPRS ratings (p=0.024). (C) vACC activation is strongly associated with the BPRS psychosis subscale (p=0.001). Linear regressions shown with 95% confidence interval, with r values indicated.

Figure 2:

Multiple axial sections of other subthreshold areas that were at peak level of p<0.001 but did not survive cluster-level FWE correction. Red corresponds to t-values>3.73 for CC-SSD comparison of the threat-safe difference. These regions include (Brodmann’s Area – BA, voxels indicate cluster size): 1. BA8/superior frontal gyrus (21 voxels), 2. BA8/medial superior frontal gyrus (100 voxels), 3. BA 40, inferolateral parietal (27 voxels), 4. BA 9/dorsolateral PFC (179 voxels), 5. BA 44/inferior frontal gyrus (47 voxels), 6. Pars orbitalis, inferior frontal cortex (159 voxels) 7. BA 21/middle temporal gyrus (14 voxels). Five other regions were not shown due to cluster sizes <10 voxels and p_FWE>0.98 for clarity, but these were located in BA 8/superior frontal gyrus (6 voxels), BA24 distinct from and lateral to the vACC activation described above (3 voxels), R insula (2 voxels), BA 10 (1 voxel), and BA 38 (1 voxel). Marker “a” indicates significant vACC activation also seen in Figure 1. No significant activations are present in the areas obscured.

Figure 3:

Association between AST-induced ACC activation (threat-safe condition) and stimulation amperage sensitivity threshold, with greater values indicating less sensitivity to pain. SSD patients (purple, p=0.014) and CC (green, p=0.77) shown. Linear regression shown with 95% confidence interval, with r values indicated.

Figure 4:

ACC activation during ankle-shock threat task (threat-safe condition) vs. trait and state depression measures in SSD patients (purple) and community controls (green). (A) Trait quantitative depression scores were significantly associated with vACC activation (p=0.043) in patients with SSD but not in controls (p=0.7) (B) State depression scores were not significantly correlated with vACC activation (SSD p>0.25, CC p>0.31). Linear regression shown with 95% confidence interval, with r values indicated.