The goals of this study were to examine the effect of the interaction between location of brain damage and MAO-A VNTR polymorphism on aggressive behaviors in subjects with PTBI, and to evaluate the effect of brain lesions and MAO-A activity on the relationship between psychological trauma and PTBI-related aggression. First, we demonstrated that PFC lesions are overrepresented in aggressive patients with PTBI compared to nonaggressive subjects with PTBI. Second, we showed an interaction between lesion localization and MAO-A activity on PTBI-related aggressive behavior. Although MAO-A low-activity allele carriers showed higher aggression than MAO-A high-activity allele carriers in the control group, the reverse effect was found in the non-PFC group, and no effect was found in the PFC group. Finally, we showed a significant association between negative childhood experiences and PTSD symptomatology and aggression levels only for the control and non-PFC groups, but not for the PFC group. Our findings seem thus to suggest that PFC structural integrity is necessary to allow other factors such as MAO-A genotype, childhood experiences, and PTSD to modulate PTBI-related aggression.
Our results in the normal group, showing a role for low-activity MAO-A allele on aggression levels, are consistent with previous studies.5,6,9,21
Absence of MAO-A activity has been shown to be related with aggressive antisocial behaviors in a Dutch kindred showing a MAO-A null point mutation6
and in MAO-A knockout animal models.21
Moreover, a seminal study of Caspi and collaborators5
showed a significant relationship between MAO-A low-activity allele and aggression subjects with negative childhood experiences. Finally, MAO-A represents one of the main modulators of serotonin levels, which are thought to play a key role in aggressive behaviors.9
Regarding the role of specific brain areas in TPBI-related aggression, our results reaffirm a key role for PFC territories in modulating aggression. Evidence of PFC involvement in aggressive behaviors has been shown in both functional neuroimaging and lesion studies.7,8,22,–25
In healthy controls, functional neuroimaging studies showed both a reduction of ventral PFC activity during mental imagery of violent acts8,22
and an increase of ventral PFC activity during inhibition of impulsive behaviors.23
Moreover, focal brain lesion studies revealed a relationship between ventral PFC structural alterations and verbal aggression in subjects with PTBI.7
However, while ventromedial PFC is thought to play a pivotal role in aggression, other PFC regions including ventrolateral PFC and cingulate cortex24,25
are thought to play an important role as well.
Aside from PTBI, our results showed that other factors such as MAO-A genotype and psychologically traumatic experiences have a crucial influence on aggressive behavior. MAO-A alleles that alter expression levels have been shown to impact prefrontal structural and functional anatomy in previous neuroimaging studies.23,25
For example, during an emotional arousal task, carriers of MAO-A low-activity alleles showed reduced orbitofrontal activity compared to subjects with high-activity alleles.25
Reduced prefrontal activity in MAO-A low-activity allele compared to high-activity allele carriers was also shown during a working memory task and during an impulse inhibition task in healthy subjects.23
As both aggressive behaviors and reduced PFC activity have been associated with reduced MAO-A activity, and as low PFC activity has been linked with aggressive behaviors, MAO-A effects on aggression should be mediated through a modulation of PFC functions. This hypothesis is to be consistent with our observation of a lack of effect of MAO genotype on aggression levels in subjects with significant prefrontal PTBI.
Consistent with this observation, we also showed both a significant correlation between aggression and early traumatic experiences and PTSD in those subjects with PTBI without PFC lesions and in controls. Like MAO-A activity, negative experiences have also been related to frontal lobe structural and functional abnormalities. Reduced frontal volume has been shown in subjects who suffered childhood sexual abuse compared to controls in a volumetric MRI study,26
while retrieval of traumatic childhood memories has been linked to reduced activations of orbitofrontal and medial frontal territories in subjects with borderline personality disorder.27
These results suggest that factors such as MAO-A genotype, early traumatic experiences, and PTSD symptoms require an intact PFC in order to have a significant influence on aggressive behavior.
Finally, we observed increased levels of aggression in those subjects with non-PFC lesions and MAO-A high-activity allele. While the role of MAO-A low activity as a susceptibility factor for aggressive behaviors has been confirmed in a recent meta-analysis,28
other studies have also shown a relationship between high MAO-A activity and clinical entities such as borderline personality disorder,29
and childhood externalizing behaviors.28
Although to date the neurobiological basis of these conditions is not completely understood, they can be collectively characterized as impulsivity and behavioral dyscontrol problems. Consistent with our results, the relationship between behavioral dyscontrol (and thus inappropriate aggression) and the MAO-A high-activity alleles could be mediated by nonfrontal areas as suggested by a functional neuroimaging study of impulse inhibition.23
In that study, the presence of the high-activity MAO-A allele correlated with reduced activation in posterior cortices, thus suggesting an effect of the MAO-A high-activity allele on posterior cortical functional anatomy.23
In our non-PFC population, the MAO-A high-activity group had a higher NPI-a score than the MAO-A low-activity group. We argue that a cumulative effect of reduced posterior cortex activity due to the MAO-A high allele23
and lesion presence in the posterior cortex leads to a lower functioning impulse inhibition network and thus to inappropriate aggression. Our hypothesis is supported by the observation that for the non-PFC group increased lesion volume was associated with higher NPI-a scores in MAO-A high-activity allele carriers. However, further studies are needed to better clarify the effects of posterior cortices activity by TPBI and MAO-A polymorphisms on the key area of aggression control, i.e., the PFC.
Our data and the evidence reported in the literature suggest that several factors including genetic polymorphisms and brain damage may modulate aggressive behaviors via altered cognitive and social processes mediated by the PFC. However, we also showed that aggression levels in subjects with prefrontal PTBI are not modulated by MAO-A activity, early life experiences, or PTSD symptomatology, even though these factors are related to aggressive behaviors in subjects with posterior brain damage (but an intact PFC) and healthy controls.
One limitation of the current study is its reliance on combat veterans, i.e., a population trained to be aggressive and then exposed to experiences of physical aggression and bodily injuries. While this common background makes our subjects more homogeneous regarding previous exposure to aggression, studies on subjects without war-related experiences are needed to validate these findings in the general population.
Moreover, given the multifaceted nature of aggression, larger studies are needed to better quantify the relative importance of environmental, genetic, and brain structural factors in aggressive behaviors in different neurologic populations.
The differences in the effects of the MAO-A VNTR polymorphism on aggression between individuals without structural brain damage and those presenting with prefrontal or nonprefrontal PTBI seems to suggest that 1) different treatment protocols might be necessary for managing inappropriate aggressive behavior in patients with prefrontal or posterior lesions and 2) other factors ranging from the severity and frequency of previous traumatic experiences to genetic polymorphisms need to be taken into consideration when determining the effects of brain damage on aggression. Future studies are warranted to evaluate the clinical relevance of our observations regarding lesion location/polymorphism-guided pharmacologic (given the possible role of MAO-A in drug responses) and behavioral approaches (given the observed differences in negative experiences/aggression relationships we observed between the lesion groups) for PTBI-related aggression.