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      Neural mechanisms of genetic risk for impulsivity and violence in humans

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          Abstract

          Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.

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          Most cited references 37

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          The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology.

          The human orbitofrontal cortex is an important brain region for the processing of rewards and punishments, which is a prerequisite for the complex and flexible emotional and social behaviour which contributes to the evolutionary success of humans. Yet much remains to be discovered about the functions of this key brain region, and new evidence from functional neuroimaging and clinical neuropsychology is affording new insights into the different functions of the human orbitofrontal cortex. We review the neuroanatomical and neuropsychological literature on the human orbitofrontal cortex, and propose two distinct trends of neural activity based on a meta-analysis of neuroimaging studies. One is a mediolateral distinction, whereby medial orbitofrontal cortex activity is related to monitoring the reward value of many different reinforcers, whereas lateral orbitofrontal cortex activity is related to the evaluation of punishers which may lead to a change in ongoing behaviour. The second is a posterior-anterior distinction with more complex or abstract reinforcers (such as monetary gain and loss) represented more anteriorly in the orbitofrontal cortex than simpler reinforcers such as taste or pain. Finally, we propose new neuroimaging methods for obtaining further evidence on the localisation of function in the human orbitofrontal cortex.
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            Primate anterior cingulate cortex: where motor control, drive and cognition interface.

             T. Paus (2001)
            Controversy surrounds the function of the anterior cingulate cortex. Recent discussions about its role in behavioural control have centred on three main issues: its involvement in motor control, its proposed role in cognition and its relationship with the arousal/drive state of the organism. I argue that the overlap of these three domains is key to distinguishing the anterior cingulate cortex from other frontal regions, placing it in a unique position to translate intentions to actions.
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              A functional polymorphism in the monoamine oxidase A gene promoter.

               S Sabol,  Stella Hu,  D. Hamer (1998)
              We describe a new polymorphism upstream of the gene for monoamine oxidase A (MAOA), an important enzyme in human physiology and behavior. The polymorphism, which is located 1.2 kb upstream of the MAOA coding sequences, consists of a 30-bp repeated sequence present in 3, 3.5, 4, or 5 copies. The polymorphism is in linkage disequilibrium with other MAOA and MAOB gene markers and displays significant variations in allele frequencies across ethnic groups. The polymorphism has been shown to affect the transcriptional activity of the MAOA gene promoter by gene fusion and transfection experiments involving three different cell types. Alleles with 3.5 or 4 copies of the repeat sequence are transcribed 2-10 times more efficiently than those with 3 or 5 copies of the repeat, suggesting an optimal length for the regulatory region. This promoter region polymorphism may be useful as both a functional and an anonymous genetic marker for MAOA.
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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                April 18 2006
                April 18 2006
                March 28 2006
                April 18 2006
                : 103
                : 16
                : 6269-6274
                Article
                10.1073/pnas.0511311103
                1458867
                16569698
                © 2006
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