Recognizing errors and adjusting responses are fundamental to adaptive behavior. The error-related negativity (ERN) and errorrelated 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. U nderstanding the nature of brain mechanisms that flexibly modify behavior in response to its outcome is a basic goal of neuroscience. Errors provide critical information for adjusting behavior to optimize outcomes. Neuroimaging studies have identified two highly reliable neural correlates of errors: the error-related negativity (ERN), an event-related potential that peaks ∼100 ms following an error, and functional MRI (fMRI) activation of the dorsal anterior cingulate cortex (dACC) for erroneous compared with correct responses (1). Both electroencephalography (EEG) and magnetoencephalography (MEG) (2) studies of the ERN have reported a source in the dACC (a list of studies is presented in Table S1), which is consistent with models that attribute these error markers to a common underlying mechanism (1, 3, 4). The primary goal of the present study was to evaluate the hypothesis of a common mechanism by determining whether the ERN is generated by the dACC region that shows error-related fMRI activation.The ERN has been extensively characterized. Its amplitude is greater when accuracy is emphasized over speed (5), when errors are corrected (6), and when errors incur greater loss (7). Larger ERNs are associated with lower error rates (3) and greater posterror slowing of responses (8). ERN latency predicts the speed of self-corrections (9). These findings suggest that the ERN is sensitive to the value of outcomes and mediates dynamic performance adjustments. Like the ERN, greater error-related fMRI activation of the dACC is associated with fewer errors (10, 11) and increased posterror slowing (12)(13)(14).Although error-related dACC activation is the putative hemodynamic reflection of the ERN (1, 4), these error markers have largely been studied separately using different samples and paradigms. The few studies that have directly investigated their relationship report correlations of fMRI activation of the ACC with the ERN and/or the error waveform or response-locked electr...

BackgroundResponding 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 FindingsUsing 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/SignificanceThese findings implicate an epigenetic mechanism in the neural response to errors, and provide insight into normal cognitive variation through a schizophrenia risk gene.

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.