Neural mechanisms of genetic risk for impulsivity and violence in humans

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.

Fig. 1.

Structural data demonstrate limbic and paralimbic regional volume changes in MAOA-L subjects (n = 97). Plots represent the summed volumes of voxels in predefined ROI, normalized to volume measures relative to the MAOA-H group mean (100%). (A) Compared with MAOA-H subjects, MAOA-L individuals exhibit significant volume reductions in bilateral amygdala, supragenual anterior cingulate, and subgenual anterior cingulate cortex. Male and female subjects were combined. (B) Male MAOA-L individuals show increased lateral orbitofrontal volume, bilaterally, relative to MAOA-H subjects. Females show no effect of genotype, resulting in a highly significant sex-by-genotype interaction.

Fig. 2.

Thresholded (P < 0.05, corrected for multiple comparisons in the ROI) statistical maps and plots of percent blood oxygen level-dependent (BOLD) signal change (mean ± 1 SEM) illustrate differential activation to angry and fearful facial expressions in MAOA-L individuals in several limbic and paralimbic regions (n = 142): subgenual anterior cingulate (BA 25) (A), supragenual anterior cingulate (BA 32) (B), left lateral OFC (BA 47) (C), and left amygdala (D).

Fig. 3.

Limbic activation during the retrieval of aversive memories varies according to MAOA genotype (n = 90). (A) Left amygdala response during emotional memory retrieval is higher for male (filled bars) MAOA-L subjects, compared with male MAOA-H individuals. (B) Left hippocampal engagement during emotional memory retrieval is more pronounced for male, but not female (open bars), MAOA-L subjects, relative to MAOA-H individuals (n = 90).

Fig. 4.

Genotype effect on anterior cingulate activation during response inhibition (no-go flanker task). Anterior cingulate (BA 32) response during response inhibition is higher for male (filled bars) MAOA-H subjects, compared with male MAOA-L individuals, whereas females (open bars) show no significant effect (n = 82).