Multimodal neuroimaging dissociates hemodynamic and electrophysiological correlates of error processing.

Recognizing errors and adjusting responses are fundamental to adaptive behavior. The error-related negativity (ERN) and error-related functional MRI (fMRI) activation of the dorsal anterior cingulate cortex (dACC) index these processes and are thought to reflect the same neural mechanism. In the present study, we evaluated this hypothesis. Although errors elicited robust dACC activation using fMRI, combined electroencephalography and magnetoencephalography data localized the ERN to the posterior cingulate cortex (PCC). ERN amplitude correlated with fMRI activation in both the PCC and dACC, and these two regions showed coordinated activity based on functional connectivity MRI. Finally, increased microstructural integrity of the posterior cingulum bundle, as measured by diffusion tensor imaging, predicted faster error correction. These findings suggest that the PCC generates the ERN and communicates with the dACC to subserve error processing. They challenge current models that view fMRI activation of the dACC as the hemodynamic reflection of the ERN.

Anomalous use of context during task preparation in schizophrenia: a magnetoencephalography study.

BACKGROUND: Impaired ability to use contextual information to optimally prepare for tasks contributes to performance deficits in schizophrenia. We used magnetoencephalography and an antisaccade task to investigate the neural basis of this deficit. METHODS: In schizophrenia patients and healthy control participants, we examined the difference in preparatory activation to cues indicating an impending antisaccade or prosaccade. We analyzed activation for correct trials only and focused on the network for volitional ocular motor control-frontal eye field (FEF), dorsal anterior cingulate cortex (dACC), and the ventrolateral and dorsolateral prefrontal cortex (VLPFC, DLPFC). RESULTS: Compared with control subjects, patients made more antisaccade errors and showed reduced differential preparatory activation in the dACC and increased differential preparatory activation in the VLPFC. In patients only, antisaccade error rates correlated with preparatory activation in the FEF, DLPFC, and VLPFC. CONCLUSIONS: In schizophrenia, reduced differential preparatory activation of the dACC may reflect reduced signaling of the need for control. Greater preparatory activation in the VLPFC and the correlations of error rate with FEF, DLPFC, and VLPFC activation may reflect that patients who are more error prone require stronger activation in these regions for correct performance. These findings provide the first evidence of abnormal task preparation, distinct from response generation, during volitional saccades in schizophrenia. We conclude that schizophrenia patients are impaired in using task cues to modulate cognitive control and that this contributes to deficits inhibiting prepotent but contextually inappropriate responses and to behavior that is stimulus bound and error prone rather than flexibly guided by context.

MTHFR 677C>T effects on anterior cingulate structure and function during response monitoring in schizophrenia: a preliminary study.

Patients with schizophrenia exhibit deficient response monitoring as indexed by blunted activation of the dorsal anterior cingulate cortex (dACC) and functionally related regions during error commission. This pattern may reflect heritable alterations of dACC function. We examined whether the hypofunctional 677C>T variant in MTHFR, a candidate schizophrenia risk gene, contributed to our previous findings of blunted error-related dACC activation and reduced microstructural integrity of dACC white matter. Eighteen medicated outpatients with schizophrenia underwent diffusion tensor imaging and performed an antisaccade paradigm during functional magnetic resonance imaging (fMRI). T allele carriers exhibited significantly less error-related activation than C/C patients in bilateral dACC and substantia nigra, regions that are thought to mediate dopamine-dependent error-based reinforcement learning. T carrier patients also showed significantly lower fractional anisotropy in bilateral dACC. These findings suggest that the MTHFR 677T allele blunts response monitoring in schizophrenia, presumably via effects on dopamine signaling and dACC white matter microstructural integrity.

A hypomethylating variant of MTHFR, 677C>T, blunts the neural response to errors in patients with schizophrenia and healthy individuals.

BACKGROUND: Responding to errors is a critical first step in learning from mistakes, a process that is abnormal in schizophrenia. To gain insight into the neural and molecular mechanisms of error processing, we used functional MRI to examine effects of a genetic variant in methylenetetrahydrofolate reductase (MTHFR 677C>T, rs1801133) that increases risk for schizophrenia and that has been specifically associated with increased perseverative errors among patients. MTHFR is a key regulator of the intracellular one-carbon milieu, including DNA methylation, and each copy of the 677T allele reduces MTHFR activity by 35%. METHODOLOGY/PRINCIPAL FINDINGS: Using an antisaccade paradigm, we found that the 677T allele induces a dose-dependent blunting of dorsal anterior cingulate cortex (dACC) activation in response to errors, a pattern that was identical in healthy individuals and patients with schizophrenia. Further, the normal relationship between dACC activation and error rate was disrupted among carriers of the 677T allele. CONCLUSIONS/SIGNIFICANCE: These findings implicate an epigenetic mechanism in the neural response to errors, and provide insight into normal cognitive variation through a schizophrenia risk gene.