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

Abstract

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.

Error processing-associated event-related potentials in schizophrenia and unaffected siblings

“…Marenco et al (2010) reported that variants of the genes for GAD1 (implicated in GABA transmission) and also COMT (responsible for the removal of dopamine from synapses in the frontal cortex) modulate GABA levels in the ACC. Of particular relevance, Roffman et al (2011) recently reported in a preliminary study of 18 cases of schizophrenia that the genetic variant MTHFR 677C>T has effects on the activation of the dorsal anterior cingulate cortex (dACC), assessed using an anti-saccade task. They concluded that their findings suggest that the MTHFR 677T allele blunts response monitoring in schizophrenia, presumably via effects on dopamine signalling and dACC white matter microstructural integrity.…”

In vivo imaging of adult human hippocampal neurogenesis: progress, pitfalls and promise

“…68 Specifically, the hippocampus in the exercising group showed stronger functionally coupling with the anterior cingulate cortex, a region known to be involved in conflict detection and resolution and response selection and monitoring. 82 …”

Neural markers of errors as endophenotypes in neuropsychiatric disorders

“…Recent work has demonstrated significant 677T allele-related reductions in error related fMRI activation of the dACC in healthy individuals and in two independent samples of patients with schizophrenia (Roffman et al, 2011a,b). The reductions in dACC activation were linearly related to allele dose regardless of diagnosis (Roffman et al, 2011b).…”