An anterior-to-posterior shift in midline cortical activity in schizophrenia during self-reflection

Abstract

Background: Deficits in social cognition, including impairments in self-awareness, contribute to the overall functional disability associated with schizophrenia. Studies in healthy subjects have shown that social cognitive functions, including self-reflection, rely on the medial prefrontal cortex (mPFC) and posterior cingulate gyrus, and these regions exhibit highly correlated activity during "resting" states. In this study, we tested the hypothesis that patients with schizophrenia show dysfunction of this network during self-reflection and that this abnormal activity is associated with changes in the strength of resting-state correlations between these regions.

Methods: Activation during self-reflection and control tasks was measured with functional magnetic resonance imaging in 19 patients with schizophrenia and 20 demographically matched control subjects. In addition, the resting-state functional connectivity of midline cortical areas showing abnormal self-reflection-related activation in schizophrenia was measured.

Results: Compared with control subjects, the schizophrenia patients demonstrated lower activation of the right ventral mPFC and greater activation of the mid/posterior cingulate gyri bilaterally during self-reflection, relative to a control task. A similar pattern was seen during overall social reflection. In addition, functional connectivity between the portion of the left mid/posterior cingulate gyrus showing abnormally elevated activity during self-reflection in schizophrenia, and the dorsal anterior cingulate gyrus was lower in the schizophrenia patients compared with control subjects.

Conclusions: Schizophrenia is associated with an anterior-to-posterior shift in introspection-related activation, as well as changes in functional connectivity, of the midline cortex. These findings provide support for the hypothesis that aberrant midline cortical function contributes to social cognitive impairment in schizophrenia.

Figure 1

The results of the anatomical region of interest (ROI) and cortical surface–based funtional magnetic resonance imaging analyses. (A) The borders of the three anatomically-defined ROI (the medial prefrontal cortex [mPFC], the middle and dorsal-posterior cingulate cortex [m/pCC], the ventral-posterior cingulate and retrosplenial cortices [pC/RSC]) are shown on this left, medial view of a representative cortical surface. These ROIs were defined in each individual subject's anatomical magnetic resonance imaging scan, using an automated parcellation system (FreeSurfer; see Methods and Materials). (B–D) Average percentage signal change during the self-reflection (SR) and affect labeling (AL) tasks, relative to a mean blood oxygen level–dependent signal intensity baseline, was extracted from the three anatomic ROIs, the mPFC (B), m/pCC (C), and pC/RSC (D). An analysis of variance revealed a significant Region by Task by Group interaction (see Results); differential responses to SR, relative to AL, were found in the mPFC in the control group (n = 17) and in the pC/RSC in the patient group (n = 18; * within-group difference, p < .05) (A, C), and significantly greater SR-related activation in the schizophrenia patients, compared with the control subjects, was found in the m/pCC region (** between-group difference, p < .05) (B). There were no activation differences between the two groups during the AL condition in any region. Error bars represent standard errors of the mean. (E–G) Cortical surface activation maps showing the activation patterns within the control (n = 17) (E) and patient (n = 18) (F) groups, and the results of the between-group comparison (G), for the SR versus AL contrast. In panels E and F, warm colors indicate vertices with significantly greater activation during SR compared with AL. There were no clusters with greater activation during AL compared with SR that met significance. In panel G, warm colors indicate vertices with significantly greater SR compared with AL activation in the control group, in comparison to the patient group, whereas cool colors indicate vertices with greater SR compared with AL activation in the patient group, in comparison to the control group. White arrows indicate the locations of between-group differences. In these analyses, the portion of the brain ventral to the corpus callosum is excluded and thus is masked in these images. R, right.

Figure 2

Group-average maps of resting-state correlations for the healthy control subjects and schizophrenia patients. Average correlation maps (Pearson's r for the control subjects [n = 19] and the patients with schizophrenia [n = 18] for the right mPFC (Talairach coordinates of seed center: 8, 42, -15) (A), left m/pCC (Talairach coordinates of seed center: -5, -30, 34) (B) and right m/pCC (Talairach coordinates of seed center: 6, -22, 32 (C), at the midline (x = 0), are displayed. Voxels that are positively correlated with the seed are labeled orange-yellow, and voxels that are negatively correlated with the seed are labeled blue. In panel A, the high degree of local positive connectivity for the right mPFC seed is evident; additional positive connectivity with the posterior cingulate gyrus (Table 3) is not visible in this slice. In panel B, the classic default mode connectivity pattern is found in both groups for the left m/pCC seed, although in the control group, connectivity of this seed extends into the dorsal mPFC, whereas for the patients, connectivity of this seed is more prominent in ventral mPFC. The location of the between-group difference in functional connectivity in the dorsal mPFC (i.e., the dorsal anterior cingulate cortex, also see Figure 3) is indicated with white arrows. In panel C, a connectivity pattern that is characteristic of the middle and dorsal-posterior cingulate cortex is seen in both groups (28). Con, control group; Scz, schizophrenia group; mPFC, medial prefrontal cortex; m/pCC, middle and dorsal-posterior cingulate cortex.

Figure 3

Sagittal (A) and coronal (B) views of the T map of control (n = 19) > schizophrenia (n = 18) functional connectivity of the left m/pCC seed, displayed at a threshold of p < .01. The Talairach × coordinate of the displayed slice is shown in the right side of each image. White arrows point to the site within the dorsal anterior cingulate cortex showing significantly greater functional connectivity with the left m/pCC seed in the control subjects, in comparison to the patients.