The MPQ aggression scale measures attitudes, values, and beliefs that are consistent with approval of the use of physical violence. Longitudinal research shows that the MPQ aggression scale empirically predicts future conviction for violent crime (Moffitt et al., 2002
) such as physical assault (Craig, 2007
). Here we report for the first time that the lower the MAO A activity in cortical and subcortical brain regions the higher the self-reported aggression, contributing to more than a third of the variability among a sample of 27 healthy men.
Since the MAO A regional activity is highly intercorrelated, we cannot make claims about the specificity in trait aggression of certain brain regions; although it appears that the correlations are stronger in cortical regions (). These results are consistent with previous imaging studies of MAO A and B. Although both types are most active in the thalamus, MAO A is relatively more active in cortical regions whereas MAO B shows more activity in subcortical regions (Fowler et al., 2005
). It is important to remember that, to avoid the confounding effects of cigarette smoking on reducing brain MAO A activity (Fowler et al., 1996
), this sample comprised of non-smoking participants. Indeed, the potential multifactorial relationship between prenatal smoking exposure and the neurochemistry underlying externalizing behaviors (e.g., impulsivity and aggression, Maughan et al., 2004
) remains to be studied. In considering the clinical implications of our findings, it is important to note that since MAO A enzymatic activity is responsible for the regulation of central serotonergic activity in terms of availability and subsequent extra-synaptic degradation [for a recent review see (Buckholtz and Meyer-Lindenberg, 2008
)] it would seemingly follow that having low MAO A activity will result in high serotonin levels. Indeed, MAO A knockout mice have high circulating serotonin (Cases et al., 1995
); however, when serotonin metabolites are examined in aggressive humans (Moffitt et al., 1998
) as well as aggressive rhesus monkeys (Howell et al., 2007
), they are found to be low. This difference is possibly due to compensatory mechanisms that primates may have developed to maintain control of high serotonin levels that could be neurotoxic (Baumgarten and Lachenmayer, 2004
). Future studies should test the interaction of serotonin and MAO A in the human brain in-vivo in order to understand their functional role in trait aggression.
Behavioral-genetic longitudinal studies have established that the low MAOA genotype predicts high trait aggression (notably using the MPQ) in men who were severely maltreated at childhood (Caspi et al., 2002
). In addition, the low MAOA genotype in healthy adults from the general population has been associated with morphological and functional changes in the amygdala (a brain region involved in expression of emotions), medial PFC (a region involved with emotional control) and in other regions that could underlie vulnerability for the expression of aggression (Meyer-Lindenberg et al., 2006
). Yet we found that neither trait aggression nor brain MAO A activity differed as a function of the MAOA genotype in the current sample, suggesting that these gene-behavior and gene-brain relationships may be developmentally mediated (Fowler et al., 2007
). It is hypothesized that at sensitive stages during early development, changes in MAO A balance triggered by a severe environmental assault could disrupt monoamine-mediated brain development leading toward the expression of an aggressive phenotype. Indeed psychosocial stress during early development is thought to play a significant role in modulating prefrontal and subcortical MAO A activity and susceptibility for aggression and impulsivity (Nelson and Trainor et al., 2007
). Because in the current study we did not assess environmental factors such as childhood stress, we cannot rule out the potential interactive contribution of the MAOA genotype to trait aggression. Clearly, the degree of exposure to stress would be an important variable to measure in future imaging studies.
While considering the multi-factor architecture of human aggression (Buckholtz and Meyer-Lindenberg, 2008
) MAO A activity in the brain provides a distinct and biological intermediate phenotype which is affected by various modifiers throughout life and is not limited by the specific polymorphism in one gene. Thus, our findings provide evidence that brain MAO A activity is a tractable target more immediate to the behavioral phenotype than the MAOA genotype stratification in healthy men. An approximate 15% reduction in brain MAO A is associated with elevated trait aggression ( and ); or put differently, brain MAO A explained more than 30% of the variability in trait aggression among these men. These findings underscore the involvement of MAO A enzymatic activity as a neurochemical target with clinical implications for the treatment of aberrant aggression.