Conflict-related anterior cingulate functional connectivity is associated with past suicidal ideation and behavior in recent-onset schizophrenia
Introduction
Schizophrenia (SZ) is a psychiatric illness with a tremendous public health impact (Murray and Lopez, 1996). Suicide is a leading cause of premature death in this illness, with those early in the illness course especially at risk (Barrett et al., 2010, Dutta et al., 2010, Ceskova et al., 2011, Pompili et al., 2011). Clinical factors associated with elevated risk of suicide in SZ include past suicidal ideation or attempts, depressive symptoms, impulsive behaviors, and possibly psychosis (Pompili et al., 2011). Overall, the total suicide rate remains stable, despite the implementation of varied suicide-prevention programs, and the widespread availability and refinement of pharmacotherapy. Knowledge of the brain circuit dysfunctions which underpin clinical expressions of suicide risk is therefore critical to advance the development of treatments, both biological and psychological, to mitigate this tragic, prevalent outcome.
Several lines of investigation in SZ indicate disturbances in the structure and function of the prefrontal cortex (PFC), which is responsible for cognitive functions that are typically grouped as executive functions. We have previously reported that PFC activity during goal-representation, an important component of executive control, is relatively lower among recent-onset schizophrenia patients with past suicidal ideation and/or behavior (Minzenberg et al., 2014b). Another critical executive function is the detection of conflict in task processes, which is necessary to optimize goal-attainment. Conflict occurs when two divergent information processes compete for attention and cognitive resources, such as when an instructed rule requires a subject to inhibit a pre-potent response tendency in favor of the task-relevant response. Resolution of conflict is thought to depend on the subject's capacity to direct attention appropriately, and also to bias either sensory and/or motor processes, each in favor of the task-relevant process. Conflict-monitoring is mediated by midline frontal regions, prominently including the dorsal ACC (dACC) and adjacent pre-supplementary motor area (pre-SMA) (Botvinick et al., 2001, Carter and van Veen, 2007). Functional neuroimaging studies in chronic and recent-onset SZ patients have shown impaired activation during conflict-monitoring in PFC regions such as the dACC (Carter et al., 1997, Kerns et al., 2005, Snitz et al., 2005, Minzenberg et al., 2009). An electroencephalographic measure of conflict-monitoring, the N450 event-related potential, which has a probable generator in the dACC (van Veen and Carter, 2002, Nieuwenhuis et al., 2003), is also impaired in SZ (McNeely et al., 2003, Minzenberg et al., 2014a). The ACC is also a key site of regional serotonergic dysfunction determined from post-mortem studies of heterogeneous suicide victim samples (reviewed in Mann (2003)). In vivo studies of varied clinical populations with elevated suicide risk (including schizophrenia patients) generally show disturbances in the ACC or functionally-connected PFC regions, of brain structure (Monkul et al., 2007, Aguilar et al., 2008, Rusch et al., 2008, Jia et al., 2010, Wagner et al., 2011, Mahon et al., 2012), function (Audenaert et al., 2002, Jollant et al., 2008, Jollant et al., 2010, Amen et al., 2009, Jollant et al., 2010, Reisch et al., 2010, Marchand et al., 2012, Zhang et al., 2013), and serotonergic functional disturbances (Oquendo et al., 2003, Frankle et al., 2005, Cannon et al., 2006). The study of control processes supported by the dACC may therefore link serotonergic dysfunction to suicide.
We therefore studied a sample of recent-onset SZ patients to test the hypothesis that altered dACC-based circuit function during conflict-monitoring is related to past suicidal ideation and behavior as measures of long-term suicide risk. These were evaluated with the Columbia Scale for the Rating of Suicide Severity (C-SSRS), a structured interview-based instrument with good validity and internal reliability in multi-site studies with diverse clinical populations (Posner et al., 2011). Rather than establishing a non-clinical comparison group, we studied a single group of SZ patients who have an elevated long-term suicide risk conferred by their diagnosis and recent-onset of overt illness. This mitigated the possibility of between-group differences in demographic or clinical factors (which could be unobserved) that might confound inferences about brain–behavior relationships in the target group. Instead, we tested relationships between conflict-related brain activation and past suicidal ideation and behavior within this single group. Importantly, in our statistical models, we controlled for the major syndromal risk factors for suicide in this population (depression, impulsivity, psychosis), in order to test direct relationships between brain function and both past suicidal ideation and behavior.
Section snippets
Subjects
The study was conducted at the Imaging Research Center at the University of California – Davis Medical Center. All procedures were approved by the UC Davis School of Medicine Institutional Review Board, and all subjects provided informed consent for all procedures. Inclusion criteria included age 18–50 years, right-handedness (by Edinburgh Handedness Inventory), and diagnosis of DSM-IV-TR 295.X, and <2 years since onset of overt psychotic illness. Exclusion criteria included neurological
Results
Please see Table 1 for subject demographic and clinical characteristics. There were few (largely non-significant) differences in demographic, clinical or task performance measures between the SI− vs SI+ subgroups, nor among SI+ patients, between SB+ vs SB− subgroups. In the neuroimaging results, the relationship of C-SSRS measures with dorsal ACC functional connectivity during conflict-monitoring showed a pattern that differed in relation to suicidal ideation compared to suicidal behavior (
Discussion
The present study represents an elaboration of our recent efforts to evaluate a model of the neural-systems basis for suicidal ideation and behavior in schizophrenia, employing a well-characterized model of control processes derived from cognitive neuroscience. We presently find that altered anterior cingulate-based neural connectivity in support of conflict-monitoring is related to both past suicidal ideation and behavior in recent-onset SZ. Importantly, these associations were evident while
Conclusion
The present findings indicate that dACC-circuit function during the monitoring of conflict is strongly associated with suicidal ideation and suicidal behavior in recent-onset schizophrenia, a condition characterized by a considerable suicide risk. This frontal-based monitoring deficit has consequences for cortical circuits that support goal-directed thought and action. The experimental methods employed here are potentially useful model-driven candidate biomarkers of pathophysiology in
Contributors
MJM and CSC designed the study and wrote the protocol. TAL, TAN, YC and RNR managed the data acquisition. MJM managed the literature searches. MJM, JHY, YC and RNR undertook the statistical analysis, and MJM wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
None declared.
Role of funding source
This work was supported by an American Foundation for Suicide Prevention Young Investigator Award, and the Doris Duke Charitable Foundation Grant # 2009045, both to MJM, and MH059883 to CSC.
Acknowledgments
We thank Madison Titone, BA, Sandra Garcia, BA, and Taylor Salo, BS for their assistance with the study data acquisition and management.
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