A Hypomethylating Variant of MTHFR, 677C&gt;T, Blunts the Neural Response to Errors in Patients with Schizophrenia and Healthy Individuals

Roffman, Joshua L.; Nitenson, Adam Z; Agam, Yigal; Isom, Marlisa; Friedman, Jesse S.; Dyckman, Kara A.; Brohawn, David G.; Smoller, Jordan W.; Goff, Donald C.; Manoach, Dara S.

doi:10.1371/journal.pone.0025253

Cited by 28 publications

(23 citation statements)

References 35 publications

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“…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). This suggests that MTHFR 677T mediates error processing in both health and schizophrenia.…”

Section: Mthfr 677c>tmentioning

confidence: 79%

Neural Markers of Errors as Endophenotypes in Neuropsychiatric Disorders

Manoach¹,

Agam²

2016

Innovations in Cognitive Neuroscience

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Learning from errors is fundamental to adaptive human behavior. It requires detecting errors, evaluating what went wrong, and adjusting behavior accordingly. These dynamic adjustments are at the heart of behavioral flexibility and accumulating evidence suggests that deficient error processing contributes to maladaptively rigid and repetitive behavior in a range of neuropsychiatric disorders. Neuroimaging and electrophysiological studies reveal highly reliable neural markers of error processing. In this review, we evaluate the evidence that abnormalities in these neural markers can serve as sensitive endophenotypes of neuropsychiatric disorders. We describe the behavioral and neural hallmarks of error processing, their mediation by common genetic polymorphisms, and impairments in schizophrenia, obsessive-compulsive disorder, and autism spectrum disorders. We conclude that neural markers of errors meet several important criteria as endophenotypes including heritability, established neuroanatomical and neurochemical substrates, association with neuropsychiatric disorders, presence in syndromallyunaffected family members, and evidence of genetic mediation. Understanding the mechanisms of error processing deficits in neuropsychiatric disorders may provide novel neural and behavioral targets for treatment and sensitive surrogate markers of treatment response. Treating error processing deficits may improve functional outcome since error signals provide crucial information for flexible adaptation to changing environments. Given the dearth of effective interventions for cognitive deficits in neuropsychiatric disorders, this represents a potentially promising approach.

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Section: Mthfr 677c>tmentioning

confidence: 79%

Neural Markers of Errors as Endophenotypes in Neuropsychiatric Disorders

Manoach¹,

Agam²

2016

Innovations in Cognitive Neuroscience

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“…MTHFR C677T may influence several steps in the DA lifecycle by regulating methylation reactions. Each copy of the 677T allele reduces MTHFR activity by 35% [21] and in two samples, error-related dACC activation was linearly related to the number of 677T alleles [9]. The 677T allele is also associated with increased risk for schizophrenia [20], and with increased severity of negative symptoms [22], worse executive function [23] and reduced dorsolateral prefrontal activation during working memory performance [24] in patients with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study

et al. 2014

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BackgroundNeuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation.MethodsWe measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response.ResultsWe replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant.Conclusions DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation.

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“…Patients with depression or schizophrenia are more likely to have common genetic variants that contribute to folate deficiency, and many of these polymorphisms are also associated with neuropsychiatric disease. The C677T MTHFR variant has been associated with an increased risk of and schizophrenia; up to 70% percent of patients with either depression or schizophrenia have been shown to carry MTHFR variants (55–57). …”

Section: The Blood-brain Barrier In Health and Diseasementioning

confidence: 99%

Folate nutrition and blood–brain barrier dysfunction

Durga¹,

Field

2017

Current Opinion in Biotechnology

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Mammals require essential nutrients from dietary sources to support normal metabolic, physiological and neuronal functions, to prevent diseases of nutritional deficiency as well as to prevent chronic disease. Disease and/or its treatment can modify fundamental biological processes including cellular nutrient accretion, stability and function in cells. These effects can be isolated to a specific diseased organ in the absence of whole-body alterations in nutrient status or biochemistry. Loss of blood-brain barrier function, which occurs in in-born errors of metabolism and in chronic disease, can cause brain-specific folate deficiency and contribute to disease co-morbidity. The role of brain folate deficiency in neuropsychiatric disorders is reviewed, as well as emerging diagnostic and nutritional strategies to identify and address brain folate deficiency in blood-brain barrier dysfunction.

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A Hypomethylating Variant of MTHFR, 677C>T, Blunts the Neural Response to Errors in Patients with Schizophrenia and Healthy Individuals

Cited by 28 publications

References 35 publications

Neural Markers of Errors as Endophenotypes in Neuropsychiatric Disorders

Neural Markers of Errors as Endophenotypes in Neuropsychiatric Disorders

Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study

Folate nutrition and blood–brain barrier dysfunction

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