In this study, we sought to determine whether activity of cortical midline regions during the appraisal of the emotional meaning of social information is abnormal in schizophrenia. We found that healthy subjects and patients with schizophrenia demonstrated opposite patterns of activity within this network. First, in the posterior cingulate gyrus, healthy subjects showed greater responses (reduced deactivation) to the negative, relative to neutral, sentence pairs, while the schizophrenia patients exhibited larger responses to the neutral, relative to the negative, sentence pairs. Second, a similar pattern was found in the relative responses of the 2 groups to the positive and neutral sentence pairs within both the medial prefrontal and posterior cingulate cortices. Third, the magnitude of responses to the neutral sentence pairs within the cingulate gyrus predicted the severity of delusional thinking in the schizophrenia patients. Finally, the patients showed a pattern of valence responsivity (positive vs negative) in the medial prefrontal cortex that was opposite to that of the healthy group; while the healthy subjects exhibited larger responses to the positively valenced sentence pairs, compared with the negative ones, in the right medial prefrontal cortex, the patients showed the reverse pattern, with greater responses to the negative compared with the positive sentence pairs in the medial prefrontal cortex bilaterally.
These results suggest that the processing of emotional information influences activity in cortical midline structures in healthy individuals and patients with schizophrenia in distinct ways. Although the precise function of the medial prefrontal and posterior cingulate cortices, and the larger default network that includes these 2 regions, is not fully understood,61
many previous functional neuroimaging studies have shown that this network is active during introspective mental activities, including self-reflection, theory-of-mind tasks, and autobiographical memory retrieval.62
Also, a number of studies have found that the performance of various cognitive tasks “turns off” or deactivates this network and that the amount of deactivation can be linked to the difficulty of the task63
or performance success.64,65
In contrast, emotional processing appears to influence activity within this network in a manner opposite to that of effortful cognitive processing, with less deactivation of the medial prefrontal cortex as emotional “load“ increases (accompanied by parallel reductions in activation of lateral prefrontal areas that mediate executive and attentional processes).66,67
Similar to emotional processing, self-referential thinking, autobiographical memory retrieval, and other types of internally directed mental activities also lead to attenuated deactivation of default network regions.62
This reciprocal modulation of the default network (and of the “task-positive” executive system) is thought to reflect dynamic changes in allocation of neural resources that serve competing demands for introspective versus externally oriented, goal-related processing.68
In the current study, the control subjects showed more activation (less deactivation) of medial prefrontal and posterior cingulate cortices in response to the emotionally laden (vs the neutral) descriptions of social situations. We also found, in a recent event-related potential (ERP) study in healthy individuals conducted using the same paradigm of the current study, a larger neurophysiological response between 500 and 700 milliseconds (the late positivity) following the emotional words, compared to the neutral ones.43
Taken together, these results indicate that, in healthy subjects, emotional processing augments both the late positivity and hemodynamic activity (attenuating deactivation) within the medial prefrontal and posterior cingulate cortices.
In patients with schizophrenia, the opposite pattern of hemodynamic findings was observed in midline cortical structures: More activation (less deactivation) was seen to the neutral than to the emotional sentence pairs. One trivial explanation for this response reversal is that, unlike controls, patients found it easier to make emotional judgments about the neutral than the emotional stimuli and therefore failed to deactivate the default network in response to the neutral sentence pairs. However, this possibility is inconsistent with our behavioral findings that indicate that, like controls, patients showed longer RTs to the neutral sentence pairs compared with the emotional ones. Thus, we attribute the reversal of response modulation in the patients to a more specific abnormality in processing emotional material.
A reversal of neural activity to emotional vs neutral material in patients is in line with the results of several previous studies, which have reported larger neural responses to neutral, nonsalient stimuli and reduced responses to aversive or reinforced stimuli in schizophrenia patients33,34
and in people at risk for schizophrenia,69
compared with healthy control subjects. This reversed hemodynamic activity was observed in the right parahippocampal gyrus during the viewing of neutral and increasingly fearful emotional facial expressions33
in the right midbrain in a reward prediction error paradigm34
and in at-risk subjects in the hippocampus, inferior and superior frontal gyri, cuneus, and thalamus during the viewing of emotional and neutral facial expressions69
. The present study extends these findings to demonstrate that this reversed modulation in schizophrenia occurs within components of the default network during appraisals of emotional and neutral socially relevant information.
In theory, this reversal of modulation to emotional vs neutral material within midline cortical structures in schizophrenia could arise from either (a
) reduced activity (increased deactivation) during the evaluation of the emotional sentence pairs, and/or (b
) increased activity (reduced deactivation) during the evaluation of the neutral sentence pairs in these regions. The current pattern of findings does not, alone, allow us to distinguish between these 2 possibilities because the baseline level of activity within these regions may have differed between the 2 groups.20,21,23
Nonetheless, on the basis of previous studies, we suggest that both (a
) and (b
) contributed to the reversed pattern of activity observed in patients.
Support for (a
)—a reduction in neural activity to the emotionally salient sentence pairs—comes from our recent ERP study in patients and controls; using this paradigm, we found a diminished late positivity response to negative and positive words in patients, compared with controls.70
Also, a number of functional neuroimaging studies have reported diminished amygdala activity in schizophrenia during appraisals of emotional facial expressions or scenes (see Aleman1
and Holt and Phillips7
Support for (b
)—an increase in activity to the neutral condition—comes from several previous fMRI studies that have detected inappropriately elevated neural responses to neutral, nonsalient stimuli in patients with schizophrenia.32–34,36
Given that, in the present study, this increased activity to neutral stimuli in patients occurred within midline cortical structures that have been found to mediate introspective mental activity, one interpretation is that in appraising the meaning of the neutral, relatively ambiguous condition, patients relied on introspective processes to a greater extent than controls.
Of note, our ERP study did not show such an increased response to neutral stimuli in patients70
; we attribute this discrepancy to the different temporal sensitivities of fMRI and ERP: neural responses to emotionally salient stimuli have been shown to occur very rapidly (detectable by ERPs and fMRI), while responses to neutral, ambiguous information may have a more extended time course that is less closely time locked to a given event (detectable by fMRI only).
The possibility that schizophrenia patients may engage in more introspective activity while appraising the meaning of neutral, ambiguous stimuli is in line with the more general hypothesis that motivational salience is misassigned to unimportant, neutral or affectively ambiguous information in schizophrenia,31,40–42,71,72
particularly in patients with active delusions. In the present study, the magnitude of the responses of the cingulate gyrus to the neutral condition correlated with delusion severity within the schizophrenia group, further supporting this hypothesis.
Nonetheless, unlike in a previous study,31
we found little behavioral evidence for elevated processing of affectively neutral information in schizophrenia or delusions. The fact that we did detect a trend toward a correlation between RTs to the neutral sentence pairs and delusions (similar to our previous finding31
) suggests that limited power, due to the smaller number of schizophrenia subjects (14) and lower percentage of neutral stimuli (33%) used here, compared with the number of schizophrenia patients (32) and percentage of neutral stimuli (50%) included in our behavioral study, could account for this discrepancy. Consistent with the findings of previous fMRI studies in schizophrenia,34,39,73,74
including 2 which showed elevated activity, but no behavioral bias, to nonsalient, neutral stimuli in patients with schizophrenia,34,39
the presence of an abnormal neural response in the absence of a parallel behavioral abnormality suggests that hemodynamic activity can, in some cases, represent a more sensitive index of neurocognitive dysfunction in schizophrenia than behavior.
In the current study, both the controls and the patients showed longer response times to the neutral compared with the emotional conditions. This was accompanied by increased activation to the neutral relative to the emotional sentence pairs, in both groups, of the dorsal anterior cingulate and lateral prefrontal cortices, 2 regions that lie outside of the default network68
(see and and Supplementary Table 2
). These increased response times and the increased activity within these 2 regions may reflect increased response competition and selection demands associated with evaluating the emotionality of the neutral sentence pairs (inherently ambiguous in this respect), in comparison to the emotional sentence pairs.75,76
Future studies that explicitly manipulate response conflict and emotional content can explore the effects of emotional and semantic ambiguity on activity within prefrontal, executive control centers in healthy subjects and patients with schizophrenia.
A related question is whether the abnormalities reported here in midline cortical structures are specific to affective processing, or are they related to a sensory or cognitive deficit(s) in schizophrenia? Although basic visual processing deficits have been linked to emotional perception impairments in schizophrenia,77,78
visual system dysfunction in schizophrenia cannot easily account for our findings because the comprehension of language occurs downstream of the visual decoding of sentences, which in our study were well matched with respect to visual features (word and sentence length and >90% of word content) across conditions.
These abnormalities also cannot be easily accounted for by general cognitive impairment. First, the pattern of response times across the patients and controls did not correspond with the pattern of modulation of midline cortical structures to emotional vs neutral sentence pairs. Second, in previous studies, abnormally elevated responses to emotionally neutral material have been observed during passive viewing conditions32,35,79
(as opposed to during a cognitive task) and when peripheral measures, rather than behavioral responses, were used as outcome variables.35,79
In addition to assessing the potential role of nonaffective processes in these abnormalities, future studies should measure neural responses during emotional appraisals of unmedicated patients experiencing acute exacerbations, in addition to those of patients with chronic symptoms, in order to determine whether these findings can be extended to acute as well as chronic psychosis and are independent of effects of medication.
An unexpected result of the current study was the abnormal response to valence (negative vs positive) within the medial prefrontal cortex in schizophrenia. In the controls, portions of the right medial prefrontal cortex showed an increased response (less deactivation) to positive vs negative sentence pairs. This finding is in line with studies conducted in rodents and nonhuman primates, as well as functional imaging studies in humans, which have shown that the orbitofrontal cortex is critical for the assessment of the valence of a stimulus; many of these studies have found that the medial orbitofrontal cortex exhibits larger responses to positive than to negative stimuli.80
However, here the patients showed a pattern of response that was opposite to that found in the controls, with larger responses to the negative relative to the positive sentence pairs. This finding is broadly consistent with evidence for abnormalities in schizophrenia in processes known to be mediated by the orbitofrontal/ventromedial cortex, such as reward-driven decision making81,82
and fear extinction recall.79
Also, several studies have reported abnormal activity levels in schizophrenia in the ventromedial83
prefrontal cortices, and in the posterior cingulate cortex,83
during tasks that rely on self-referential processing, suggesting that dysfunction of this midline cortical network may disrupt social cognitive processes in schizophrenia. Given that delusions often appear to arise from errors in social attributions, in particular, misassignments of self-relevance, these data suggest that such errors could be related to impaired functioning of these midline cortical regions during delusion formation.
In conclusion, we have shown that key components of a cortical midline network, the posterior cingulate and medial prefrontal cortices, are abnormally modulated during appraisals of the emotional meaning of social information in schizophrenia. Future studies that compare individuals with psychotic symptoms who are at different stages of the illness can determine whether dysfunction of this network represents a consequence of, or a marker of vulnerability to, psychosis.