In this study, patients with schizophrenia showed abnormally elevated activation of the right and left m/pCC during self-reflection, compared to a low-level baseline and to responses during a nonintrospective task. Also, in a cortical surface-based analysis, the schizophrenia patients showed abnormally reduced responses during self-reflection, compared with a nonintrospective task, within the right ventral mPFC. Lastly, this abnormal pattern of task-dependent activation in schizophrenia was accompanied by decreased functional connectivity between the left m/pCC and the dorsal anterior cingulate gyrus and, at a more liberal threshold, increased connectivity between the right and left m/pCC and the ventral mPFC, in schizophrenia patients compared with control subjects.
It is noteworthy that the elevation in activity of the m/pCC in the schizophrenia patients was detected in both of the task-based fMRI analyses (the anatomic ROI and the cortical surface–based), whereas the reduced mPFC response in the patients was found only in the cortical surface–based analysis. Because the between-group difference in the m/pCC was detected even when activation was averaged over a large, anatomically defined ROI, it is likely that the bilateral m/pCC exhibits a generalized, widespread elevation in activity during self-reflection in schizophrenia patients. Because the cortical surface–based analysis is more sensitive to spatially restricted effects, the finding of a between-group difference in the right mPFC here but not in the ROI analysis suggests that only a portion of the large mPFC ROI showed abnormal responses in schizophrenia during self-reflection, and that this abnormality is likely smaller in magnitude or less consistent in spatial location across subjects than the change in m/pCC function in schizophrenia.
Previous studies of the function of this midline network in schizophrenia during social cognitive tasks have also reported abnormally reduced activation of the mPFC, most frequently within the right hemisphere, in schizophrenia. This abnormality has been observed during performance of theory-of-mind tasks (36
), empathy and forgivability judgments (38
), facial affect discrimination (25
), and retrieval of self-generated information (39
). In contrast, during attention-demanding, executive control tasks, both hypoactivation (arising from greater task-induced deactivation [TID] in the patients) (40
) and hyperactivation (arising from weaker TID in the patients) (42
) of the mPFC in schizophrenia has been reported. The inconsistencies among these previous results are likely due to variation across studies in the difficulty of the executive tasks performed and the related variation in performance differences between the healthy and schizophrenia subjects. In the current study, the control subjects showed the expected pattern of response in the mPFC (less TID during self-reflection relative to affect labeling), whereas the patients with schizophrenia showed pronounced deactivation of the right mPFC during both tasks. The greater TID of the right mPFC during self-reflection in the schizophrenia patients, compared with the control subjects, could reflect greater effort or attentional engagement during self-reflection; however, this possibility is unlikely given that the mean response times during self-reflection (and mean IQ) of the two groups did not differ. Given that introspective activity typically lessens deactivation of the mPFC (12
), this finding could reflect diminished introspective activity in schizophrenia (45
Although the two groups in this study did not differ on mean reaction times and response types, the accuracy
of the self-ratings was not measured here; such an index of self-awareness might be more closely linked to the magnitude of neural responses during self-reflection than reaction times or response types during the task. Although admittedly difficult to measure, this type of accuracy has been estimated previously by measuring the concordance between ratings given by participants of the self-descriptiveness of traits and ratings given by relatives or caregivers of the participants (46
). Follow-up studies could include such a measure to determine whether impaired self-awareness in schizophrenia predicts dysfunction of the mPFC and/or m/pCC.
Our results are consistent with the findings of two previous studies that detected elevated responsivity of the posterior cingulate gyrus in schizophrenia during social perception tasks (25
). Interestingly, the overall anterior-to-posterior shift in neural activity in schizophrenia observed here mirrors the effects of N
-methyl-D-aspartate glutamate receptor blockade, a popular pharmacologic model of schizophrenia, on the BOLD signal (47
), as well as positron emission tomography findings of abnormally reduced mPFC activity and increased posterior cingulate cortex activity in schizophrenia (48
). The current study indicates that this shift in midline cortical activity in schizophrenia occurs during social reflection.
It is important to note that much of the posterior cingulate gyrus found to show abnormally elevated responsivity in the schizophrenia group here () is dorsal and anterior to the region that typically exhibits activity during self-reflection in healthy subjects (19
). This dorsal area most likely corresponds to the posterior midcingulate and dorsal posterior cingulate gyrus, according to Vogt's eight-compartment model of the cingulate gyrus (29
). The pattern of functional connectivity of the right m/pCC site showing greater activation in the patients compared to controls (prominent intracingulate functional connectivity; ) is also consistent with this designation (27
). Although the precise function of this region is not fully understood, previous fMRI studies indicate that the medial parietal lobe, including this dorsal portion of the posterior cingulate gyrus, is involved in functions that rely on spatial memory and visuospatial orientation, such as the navigation of the body in space (27
) and first-person (vs. third-person) perspective taking (52
). The medial parietal lobe is also recruited during episodic and autobiographical memory retrieval tasks, particularly when subjects are asked to recall specific details of past events (53
). In light of this literature, one possible interpretation of our results is that patients with schizophrenia rely to a greater extent than healthy subjects on visuospatial simulation and retrieval of specific episodic memories to make judgments about whether trait adjectives describe themselves, whereas during the same task, healthy subjects need only retrieve overlearned, abstracted information about themselves (46
). Supporting this possibility is recent work suggesting that the mPFC is associated with the retrieval and storage of semantic aspects of self-knowledge (such as information about one's traits), whereas the pCC mediates retrieval of concrete, imageable details about the self (such as one's physical characteristics) (54
Analyses of additional contrasts in the current study revealed that overall social introspection (responses during self-reflection combined with responses during other-reflection) produced a pattern of results that was similar to the findings of the primary analysis, but there were no between-group differences found when self-reflection was directly contrasted with other-reflection. These results support the possibility that the abnormality in midline cortical function in schizophrenia during self-reflection is due to a general deficit in introspection or social cognition. However, these secondary analyses must be interpreted with caution because our study used a block design (to maximize power to detect differences between the groups); previous work suggests that differences detected between the neural correlates of self- and other-reflection may be greater in studies which used event-related designs (18
). Follow-up event-related studies can determine whether the anterior-to-posterior shift in midline cortical function in schizophrenia seen here is most prominent during self-referential thinking or associated with a range of social cognitive processes.
The reduction in functional connectivity found in the schizophrenia group between the m/pCC and dorsal anterior cingulate gyrus is consistent with a large body of prior evidence for diminished connectivity and neural synchrony in schizophrenia (57
). However, at a lower statistical threshold, we also found elevations in intrinsic functional connectivity between the m/pCC bilaterally and the ventral mPFC. Similarly, a previous study reported abnormally elevated functional connectivity of the mPFC in schizophrenia patients, as well as in first-degree relatives of patients with schizophrenia, within the default network (44
). Additional studies that measure connectivity using complementary methods, while controlling for data acquisition-related confounds, will be needed to clarify the precise nature of the changes in default network connectivity in schizophrenia.
In summary, in this study, abnormally elevated activity within the m/pCC and reduced activity of the right ventral mPFC was found in patients with schizophrenia during social reflection. In the same patients, abnormalities in resting-state functional connectivity within this network were also observed. Future studies can test whether some or all of these abnormalities could serve as quantitative neural markers of the social cognitive deficits associated with schizophrenia.