Modulating effect of COMT genotype on the brain regions underlying proactive control process during inhibition

peer reviewedIntroduction. Genetic variability related to the catechol-O-methyltransferase (COMT) gene (Val158Met polymorphism) has received increasing attention as a possible modulator of cognitive control functions. Methods. In an event-related fMRI study, a modified version of the Stroop task was administered to three groups of 15 young adults according to their COMT Val158Met genotype [Val/Val (VV), Val/Met (VM) and Met/Met (MM)]. Based on the theory of dual mechanisms of control (Braver, et al., 2007), the Stroop task has been built to induce proactive or reactive control processes according to the task context. Results. Behavioral results did not show any significant group differences for reaction times but Val allele carriers individuals are less accurate in the processing of incongruent items. fMRI results revealed that proactive control is specifically associated with increased activity in the anterior cingulate cortex (ACC) in carriers of the Met allele, while increased activity is observed in the middle frontal gyrus (MFG) in carriers of the Val allele. Conclusion. These observations, in keeping with a higher cortical dopamine level in MM individuals, support the hypothesis of a COMT Val158Met genotype modulation of the brain regions underlying proactive control, especially in frontal areas as suggested by Braver et al

EEG Source Imaging Indices of Cognitive Control Show Associations with Dopamine System Genes.

Cognitive or executive control is a critical mental ability, an important marker of mental illness, and among the most heritable of neurocognitive traits. Two candidate genes, catechol-O-methyltransferase (COMT) and DRD4, which both have a roles in the regulation of cortical dopamine, have been consistently associated with cognitive control. Here, we predicted that individuals with the COMT Met/Met allele would show improved response execution and inhibition as indexed by event-related potentials in a Go/NoGo task, while individuals with the DRD4 7-repeat allele would show impaired brain activity. We used independent component analysis (ICA) to separate brain source processes contributing to high-density EEG scalp signals recorded during the task. As expected, individuals with the DRD4 7-repeat polymorphism had reduced parietal P3 source and scalp responses to response (Go) compared to those without the 7-repeat. Contrary to our expectation, the COMT homozygous Met allele was associated with a smaller frontal P3 source and scalp response to response-inhibition (NoGo) stimuli, suggesting that while more dopamine in frontal cortical areas has advantages in some tasks, it may also compromise response inhibition function. An interaction effect emerged for P3 source responses to Go stimuli. These were reduced in those with both the 7-repeat DRD4 allele and either the COMT Val/Val or the Met/Met homozygous polymorphisms but not in those with the heterozygous Val/Met polymorphism. This epistatic interaction between DRD4 and COMT replicates findings that too little or too much dopamine impairs cognitive control. The anatomic and functional separated maximally independent cortical EEG sources proved more informative than scalp channel measures for genetic studies of brain function and thus better elucidate the complex mechanisms in psychiatric illness

COMT Val158Met Polymorphism Exerts Sex-Dependent Effects on fMRI Measures of Brain Function

Evidence suggests that dopamine levels in the prefrontal cortex (PFC) modulate executive functions. A key regulator of PFC dopamine is catechol-O-methyltransferase (COMT). The activity level of the COMT enzyme are influenced by sex and the Val158Met polymorphism (rs4680) of the COMT gene, with male sex and Val alleles both being associated with higher bulk enzyme activity, and presumably lower PFC dopamine. COMT genotype has not only been associated with individual differences in frontal dopamine-mediated behaviors, but also with variations in neuroimaging measures of brain activity and functional connectivity. In this study, we investigated whether COMT genotype predicts individual differences in neural activity and connectivity, and whether such effects are sex-dependent. We tested 93 healthy adults (48 females), genotyped for the Val158Met polymorphism, in a delay discounting task and at rest during fMRI. Delay discounting behavior was predicted by an interaction of COMT genotype and sex, consistent with a U-shaped relationship with enzyme activity. COMT genotype and sex similarly exhibited U-shaped relationships with individual differences in neural activation, particularly among networks that were most engaged by the task, including the default-mode network. Effects of COMT genotype and sex on functional connectivity during rest were also U-shaped. In contrast, flexible reorganization of network connections across task conditions varied linearly with COMT among both sexes. These data provide insight into the potential influences of COMT-regulated variations in catecholamine levels on brain function, which may represent endophenotypes for disorders of impulsivity

EEG Source Imaging Indices of Cognitive Control Show Associations with Dopamine System Genes

Cognitive or executive control is a critical mental ability, an important marker of mental illness, and among the most heritable of neurocognitive traits. Two candidate genes, catechol-O-methyltransferase (COMT) and DRD4, which both have a roles in the regulation of cortical dopamine, have been consistently associated with cognitive control. Here, we predicted that individuals with the COMT Met/Met allele would show improved response execution and inhibition as indexed by event-related potentials in a Go/NoGo task, while individuals with the DRD4 7-repeat allele would show impaired brain activity. We used independent component analysis (ICA) to separate brain source processes contributing to high-density EEG scalp signals recorded during the task. As expected, individuals with the DRD4 7-repeat polymorphism had reduced parietal P3 source and scalp responses to response (Go) compared to those without the 7-repeat. Contrary to our expectation, the COMT homozygous Met allele was associated with a smaller frontal P3 source and scalp response to response-inhibition (NoGo) stimuli, suggesting that while more dopamine in frontal cortical areas has advantages in some tasks, it may also compromise response inhibition function. An interaction effect emerged for P3 source responses to Go stimuli. These were reduced in those with both the 7-repeat DRD4 allele and either the COMT Val/Val or the Met/Met homozygous polymorphisms but not in those with the heterozygous Val/Met polymorphism. This epistatic interaction between DRD4 and COMT replicates findings that too little or too much dopamine impairs cognitive control. The anatomic and functional separated maximally independent cortical EEG sources proved more informative than scalp channel measures for genetic studies of brain function and thus better elucidate the complex mechanisms in psychiatric illness

The impact of Catechol-O-Methyl transferase on working memory in psychometrically identified schizotypy

Patients with schizophrenia often exhibit impairment in working memory that is influenced by dopamine availability in the prefrontal cortex. Dopamine availability in the prefrontal cortex is regulated in part by the activity of the Catechol-O-Methyl transferase (COMT) gene. The COMT gene contains a functional polymorphism that results in a Valine (Val) to Methionine (Met) amino acid substitution that impacts dopamine availability. COMT impacts working memory performance in patients with schizophrenia such that Val allele load is associated with impaired working memory performance. The present study extended this literature by examining the relationship between COMT and spatial working memory (SWM), and their interactions, in psychometrically identified positive and negative schizotypy in a nonclinically ascertained sample of young adults. As hypothesized, negative schizotypy was associated with the Val allele in an allele dependent fashion. In addition, negative, but not positive, schizotypy was generally associated with deficits in SWM performance. Contrary to hypotheses, poorer SWM was not associated with Val allele load. Additionally, COMT generally did not moderate the relations between SWM and negative schizotypy. The findings support the idea that the neurodevelopmental vulnerability for schizophrenia is expressed across a continuum of impairment referred to as schizotypy, the construct validity of a multidimensional model of schizotypy, and the use of psychometric screening inventories as promising tools to help understand the etiology and development of schizophrenia

Age-Related Decline in Brain Resources Modulates Genetic Effects on Cognitive Functioning

Individual differences in cognitive performance increase from early to late adulthood, likely reflecting influences of a multitude of factors. We hypothesize that losses in neurochemical and anatomical brain resources in normal aging modulate the effects of common genetic variations on cognitive functioning. Our hypothesis is based on the assumption that the function relating brain resources to cognition is nonlinear, so that genetic differences exert increasingly large effects on cognition as resources recede from high to medium levels in the course of aging. Direct empirical support for this hypothesis comes from a study by Nagel et al. (2008), who reported that the effects of the Catechol-O-Methyltransferase (COMT) gene on cognitive performance are magnified in old age and interacted with the Brain-Derived Neurotrophic Factor (BDNF) gene. We conclude that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. Extensions of the hypothesis to other polymorphisms are discussed. (150 of 150 words

The Role of COMT in Schizophrenic-Like Cognitive Impairment and Social Functioning in Children with 22q11 Deletion Syndrome

Schizophrenia is a severe psychiatric disorder that is hypothesized to represent the most extreme manifestation of a continuum of impairment referred to as schizotypy. As such, many of the cognitive, clinical, behavioral, and neuroanatomical features of schizophrenia should be present and detectable in nonpsychotic individuals who share this vulnerability. Recent findings have led to a renewed interest in the role that the gene that codes for catechol-O-methyltransferase (COMT) plays in the development and expression of schizotypy and schizophrenia. Specifically, an amino-acid polymorphism (Val158Met) in the COMT gene has been associated with schizophrenia based on linkage and association studies, with schizotypy in nonpsychotic adults, and with performance on dopamine-mediated prefrontal functioning in healthy adults and in patients with schizophrenia. Since abnormal functioning in dopaminergic pathways is thought to be associated with schizophrenia, COMT activity may play a role in schizophrenia pathogenesis and expression. The COMT gene is housed at 22q11.2, which maps to the commonly deleted region in 22q11 Deletion Syndrome (22q11DS), a syndrome that is associated with a highly elevated risk for the development of psychosis. The present study investigated the relationship of COMT genotype with neuropsychological impairment and social functioning in a nonpsychotic sample of children with 22q11DS. As hypothesized, participants with the Val allele performed worse on some measures of prefrontal functioning than participants with the Met allele. Additionally, participants with the Val allele exhibited schizophrenic-like social and behavioral deficits. Finally, associations between social and cognitive functioning and a haplotype that has been linked to schizophrenia were examined in patients with 22q11DS

Genetic influences on emotion/cognition interactions : from synaptic regulation to individual differences in working memory for emotional faces

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