Both individuals with NP-SCZ and healthy comparison participants showed significantly greater activation of the examined social cognitive network when a face was judged to be untrustworthy relative to trustworthy, thus demonstrating neural sensitivity to threatening social stimuli. Paranoid individuals with schizophrenia, however, failed to show any modulation of neural activation for untrustworthy faces relative to trustworthy faces. These findings further our previous work by demonstrating that reduced neural activation for paranoid individuals during trustworthiness evaluations are specific to faces perceived as untrustworthy. The fact that groups showed comparable levels of activation for trustworthy faces indicates that the impairments seen in P-SCZ are not due to global reductions in activation but rather to a lack of normative increases in activation to threatening stimuli.
Results of this study are also consistent with previous work highlighting fundamental distinctions in neural activation between schizophrenia subgroups. Earlier studies showed relatively intact AMYG and MPFC activation for nonparanoid individuals during implicit processing of emotion,22–24
and here, we replicate those findings with a task of complex social cognition and extend them to the VLPFC. More normative activation for NP-SCZ (relative to P-SCZ) in several regions of the examined social cognitive circuit demonstrates that these differences between subgroups are widespread and emphasize the distributed and interactive nature of this social cognitive network.
In contrast, the only region where P-SCZ and NP-SCZ resembled each other was in bilateral FG. Here, neither group showed a significant increase in activation for untrustworthy faces, although it should be noted that the increases evident in the NP-SCZ approached significance (L FG: P
.115, and R FG: P
.073). Although speculative, this may suggest that all individuals with schizophrenia have some degree of impairment in the direct feedback connections from AMYG to FG43
that would increase FG activation once the AMYG has designated a stimulus to be threatening. This finding may also shed light on previous studies reporting reduced activation of the right lateral FG in schizophrenia during emotion perception tasks as compared with healthy individuals.44–46
It is possible that heightened FG responses to threatening emotions (ie, anger and fear) in controls may have driven these group differences.
Further, examination of behavioral responses revealed that the groups generally agreed in their assessments of trustworthiness but that paranoid individuals were more likely to rate a face as untrustworthy. The agreement between groups indicates that the majority of stimuli were included in the same category across groups and that the apparent differences in neural activation are not a function of random responding or largely different categorizations of faces. Rather, the integration of the behavioral and neural data may provide insights into the nature of paranoia. The lack of modulation seen in P-SCZ demonstrates that, at the neural level, all faces were processed similarly despite the fact that these individuals were able to behaviorally categorize faces as trustworthy or untrustworthy in a manner that was largely consistent with control and NP-SCZ participants (albeit while rating more faces as untrustworthy). Increased behavioral ratings of mistrust without concurrent increases in neural activation are consistent with findings of a disconnect between autonomic arousal systems and neural response in which paranoid individuals show enhanced arousal coupled with reduced AMYG activation when viewing threat-related stimuli.23
These findings may indicate that the neural mechanisms of threat appraisal are ineffective in paranoid individuals and that while retaining the ability to make gross distinctions between stimuli at a behavioral level, paranoid individuals may be unable to make fine-grained distinctions, which may contribute to the over attribution of threat seen in paranoid ideation. Alternately, these findings could reflect habituation of AMYG activity in paranoid individuals, suggesting that threatening stimuli may lose saliency over time; however, this interpretation is somewhat contradictory to the noted findings of increased autonomic arousal in P-SCZ. Nevertheless, these findings certainly require further investigation.
In addition to having implications for schizophrenia, the present study also furthers our understanding of the examined social cognitive neural network. Increased AMYG, FG, and STS activation to untrustworthy faces in healthy individuals was expected and is consistent with previous work.29,30
Greater AMYG activation to untrustworthy faces is likely related to this region's role in detecting threat19
and orienting to salient information,47,48
and as noted previously, increased FG activation is likely due to modulatory influences from the AMYG via back projections.43
Differential activation of the STS may be explained by its involvement in theory of mind inferences.30
Given that one may attempt to infer the intentions of another as a means of evaluating whether they can be trusted and that uncertainty about these intentions may lead to a judgment of untrustworthiness, such a process may explain the differential activation seen here.
Findings from this study also extend those of Winston et al.30
by demonstrating increased activation of frontal regions, specifically the MPFC and bilateral VLPFC, in nonclinical controls for untrustworthy faces. These findings suggest that both regions are sensitive to differing levels of perceived threat. For the MPFC increased activation for untrustworthy faces may reflect more emphasis on determining the intentions of pictured individuals who appear more likely to pose a threat. For VLPFC, greater activation during untrustworthiness judgments may reflect this region's role in modulating and regulating emotional responses.27,49
Such an interpretation is consistent with work showing that extended cognitive evaluation of emotional stimuli is associated with relative decreases in AMYG response and correlated increases in VLPFC activation, as compared with brief stimulus presentations.27,28
Of primary importance, across all groups, neural activation within this social cognitive network, and in particular the degree of modulation between trustworthy and untrustworthy faces, was positively correlated with social functioning. These relationships were evident in both frontal regions investigated (ie, MPFC and VLPFC) and also in the FG. Unexpectedly, a significant relationship with social functioning was not found for AMYG activation when groups were examined conjointly. This may be explained by work with healthy individuals demonstrating that AMYG response during trustworthiness evaluations is more closely related to consensus ratings of trustworthiness rather than idiosyncratic judgments.29
Thus, we may not have assessed activation in a way that maximally measures the AMYG response. Our decision to examine participant responses was made a priori based on anticipated differences between the judgments of schizophrenia subgroups and a desire to link neural activation to behavioral responses. Also unexpectedly, the clinical groups did not show the same strength of relationships between modulation of neural activation and social functioning. This may be partially explained by the increased variability in the clinical groups (eg, SFS range: controls 140–193, NP-SCZ 104–179, and P-SCZ 97–168) and the small sample sizes. Nevertheless, the significant correlations between greater modulation of activation and better social functioning across groups and the positive (albeit nonsignificant) correlations within the clinical groups indicate that the amount of neural modulation while processing social stimuli has potential to become a predictive marker of real-world social behavior. These relationships also highlight the direct connections between social cognition and social functioning.
Although the present study elucidates the nature of neural abnormalities in P-SCZ, a number of questions require further clarification. First, although the SCZ subgroups did not differ in chlorpromazine equivalents, the effects of medication were not assessed. Second, given recent work in autism demonstrating that neural activation in the AMYG is associated with visual scanning of the eye region of faces50
but work in schizophrenia showing reductions in AMYG activation even when faces are not consciously perceived,51
it is unknown what role visual face scanning patterns may have played in the present results. Likewise, it is unclear what effect autonomic arousal may have had on both neural activation and behavioral ratings. Future work would benefit from including concurrent eye-tracking and physiological monitoring to investigate these effects. Third, the 2 schizophrenia subgroups did not significantly differ from each other on social functioning, which is unexpected given the reported differences in neural activation. It is possible that the self-report format and the wide scope of functioning assessed by the SFS may have limited our ability to discern group differences in social behaviors that may be more proximal to social cognition (ie, social skill as opposed to independent living skills). Additionally, all clinical participants in this study were stable outpatients, which may have also contributed to the lack of significant group differences in overall social functioning. Finally, in order to assess multiple groups, the number of individuals who could be enrolled in each group was necessarily limited, and only right-handed male participants were recruited. These factors may limit the generalizability of the results and indicate that replication is needed.
Notwithstanding these limitations, the present study reports a novel observation related to the processing of threat-related social information in schizophrenia subgroups. The finding that paranoid individuals with schizophrenia failed to show normative increases in neural activation when they judged a face to be untrustworthy reveals an important distinction between schizophrenia subgroups and may shed light on the nature of paranoid ideation by demonstrating impairments in the neural mechanisms of threat appraisal in paranoid individuals. Moreover, the amount of neural modulation between trustworthy and untrustworthy stimuli within the examined social cognitive network was significantly and positively correlated to social functioning. These findings suggest that remediation of this response may aid in improving social behavior and emphasize the importance of social cognition for functional outcome.