Prefrontal cortex lesions and MAO-A
modulate aggression in penetrating
traumatic brain injury
M. Pardini, MD
F. Krueger, PhD
C. Hodgkinson, PhD
V. Raymont, MD
C. Ferrier, MA
D. Goldman, MD
M. Strenziok, PhD
S. Guida, MD
J. Grafman, PhD
Objective: This study investigates the interaction between brain lesion location and mono-
amine oxidase A (MAO-A) in the genesis of aggression in patients with penetrating traumatic
brain injury (PTBI).
Methods: We enrolled 155 patients with PTBI and 42 controls drawn from the Vietnam Head
Injury Study registry. Patients with PTBI were divided according to lesion localization (prefrontal
cortex [PFC] vs non-PFC) and were genotyped for the MAO-A polymorphism linked to low and high
transcriptional activity. Aggression was assessed with the aggression/agitation subscale of the
Neuropsychiatric Inventory (NPI-a).
Results: Patients with the highest levels of aggression preferentially presented lesions in PFC
territories. A significant interaction between MAO-A transcriptional activity and lesion local-
ization on aggression was revealed. In the control group, carriers of the low-activity allele
demonstrated higher aggression than high-activity allele carriers. In the PFC lesion group, no
significant differences in aggression were observed between carriers of the 2 MAO-A alleles,
whereas in the non-PFC lesion group higher aggression was observed in the high-activity
allele than in the low-activity allele carriers. Higher NPI-a scores were linked to more severe
childhood psychological traumatic experiences and posttraumatic stress disorder symptom-
atology in the control and non-PFC lesion groups but not in the PFC lesion group.
Conclusions: Lesion location and MAO-A genotype interact in mediating aggression in PTBI. Im-
portantly, PFC integrity is necessary for modulation of aggressive behaviors by genetic suscepti-
be combined to develop risk-stratification algorithms and individualized treatments for aggres-
sion in PTBI. Neurology®2011;76:1038–1045
AFQT ? Armed Forces Qualification Test; ANCOVA ? analysis of covariance; BDI ? Beck Depression Inventory; CAPS ?
Clinician-Administered PTSD Scale; DSM-IV-TR ? Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text
revision; ETI ? Early Trauma Inventory; MAO-A ? monoamine oxidase A; NPI-a ? aggression/agitation subscale of the
Neuropsychiatric Inventory; PFC ? prefrontal cortex; PTBI ? penetrating traumatic brain injury; PTSD ? posttraumatic
stress disorder; VHIS ? Vietnam Head Injury Study; VNTR ? variable number tandem repeat.
Aggressive behavior is a common problem following penetrating traumatic brain injury
(PTBI), reported by at least a third of patients with PTBI.1Aggression has been linked to
different pathogenetic mechanisms, including brain alterations, psychological trauma, and ge-
netic susceptibilities.2The relative roles and the interactions between these factors, however,
are only partially understood.
From the Cognitive Neuroscience Section (M.P., F.K., V.R., M.S., J.G.), National Institute of Neurological Disorders and Stroke–NIH,
Bethesda, MD; Department of Neurosciences, Ophthalmology and Genetics (M.P., S.G.), and Magnetic Resonance Research Centre on
Nervous System Diseases (M.P.), University of Genoa, Genoa, Italy; Department of Molecular Neuroscience (F.K.), George Mason University,
Fairfax, VA; Laboratory of Neurogenetics (C.H., C.F., D.G.), National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD; and
Department of Radiology (V.R.), Johns Hopkins University, Baltimore, MD. J.G. is currently with the Brain Injury Research Laboratory,
Kessler Foundation Research Center, West Orange, NJ.
Study funding: Supported by the US National Institute of Neurological Disorders and Stroke intramural research program and a project grant from the
US Army Medical Research and Material Command administered by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: a
30-year postinjury follow-up study).
Disclosure: Author disclosures are provided at the end of the article.
The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy,
the Department of Defense, or the US Government.
Address correspondence and
reprint requests to Dr. Jordan
Grafman, Brain Injury Research
Laboratory, Kessler Foundation
Research Center, 1199 Pleasant
Valley Way, West Orange,
Copyright © 2011 by AAN Enterprises, Inc.
One of the genes that has been linked with
aggression is the monoamine oxidase A
(MAO-A) gene,3which catalyzes oxidative
deamination of amines. Compared to MAO-B,
MAO-A presents with a higher affinity for sero-
to be more involved in pathologic aggression.2,3
Among the polymorphic sites described in the
MAO-A gene, a common variable number tan-
dem repeat (VNTR) polymorphism is thought
to be particularly relevant for aggression. This
polymorphism encodes 2 distinct functional
variants: 1) a high-activity (3.5 and 4 repeats)
and 2) a low-activity allele (2, 3, and 5 repeats).4
The low-activity allele compared with the high-
activity variant has been shown to present with
relatively lower transcriptional activity4and to
be potentially related to aggressive behaviors.3,5,6
Pathologic aggression has been associated with
prefrontal cortex (PFC) alterations in ventro-
medial areas7but also in the orbitofrontal
and anterior cingulate cortices,2,7-9suggest-
ing a pivotal role for a complex PFC-based
network in aggression.
The goal of this study was to examine the
effect of the interaction between location of
brain damage and the MAO-A VNTR poly-
morphism on aggressive behaviors in subjects
with PTBI and their impact on the relation-
ship between psychological trauma and
METHODS Subjects and behavioral evaluation. En-
rolled subjects were drawn from the Vietnam Head Injury
Study (VHIS) phase 3 registry as described elsewhere.10We
conducted phase 3 between 2003 and 2006 at Bethesda Na-
tional Naval Medical Center (36–39 years postinjury). Each
subject underwent neurologic and psychiatric examinations
and a noncontrast brain CT scan. Preinjury characteristics
and clinical follow-up data of the participants were available
from military and Veterans Administration records. Subjects
with a diagnosis of alcohol or substance abuse disorder, de-
mentia, or psychotic disorder as assessed by clinical data were
not considered eligible.
We enrolled 155 male Vietnam-era veterans with PTBI due
to low-velocity missile wounds. These subjects were divided into
2 groups according to the involvement of PFC territories (see
below): the PFC lesion group (106 subjects) and the non-PFC
lesion group (49 subjects). We also enrolled 42 healthy male
subjects who served in Vietnam but did not sustain brain inju-
ries. Demographic and clinical data (table) showed no differ-
ences in age (F2,194? 2.8; p ? 0.06), education (F2,194? 2.5;
p ? 0.08), ethnicity (Pearson ?2? 1.0; p ? 0.81), preinjury IQ
(F2,194? 2.0; p ? 0.08) as assessed with the Armed Forces
Qualification Test (AFQT),10or depression (F2,194? 1.8; p ?
0.16) assessed with the Beck Depression Inventory (BDI-II)11
among the 3 groups (PFC lesion, non-PFC lesion, controls).
Table Demographic and neuropsychological data for the experimental and control groups
NPI-a Age, y
No. of PTSD-
PFC lesion group, all subjects
(n ? 106 subjects)
1.2 ? 0.258.2 ? 0.398/8 14.5 ? 0.258.1 ? 2.29.1 ? 0.84.7 ? 0.34.3 ? 0.4
PFC lesion group, MAO-A high
activity (n ? 65 subjects)
1.1 ? 0.3 58.1 ? 0.461/414.6 ? 0.358.2 ? 2.9 8.4 ? 1.04.9 ? 0.54.3 ? 0.3
PFC lesion group, MAO-A low
activity (n ? 41 subjects)
1.2 ? 0.358.5 ? 0.6 37/414.3 ? 0.257.0 ? 3.9 9.4 ? 1.44.5 ? 0.44.2 ? 0.7
Non-PFC lesion group, all
subjects (n ? 49 subjects)
1.2 ? 0.358.5 ? 0.344/515.3 ? 0.365.5 ? 3.9 12.0 ? 1.5 6.1 ? 0.74.7 ? 0.4
Non-PFC lesion group, MAO-A
high activity (n ? 29 subjects)
1.7 ? 0.259.4 ? 0.726/3 15.5 ? 0.561.3 ? 5.1 10.6 ? 1.75.9 ? 0.9 4.9 ? 0.6
Non-PFC lesion group, MAO-A
low activity (n ? 20 subjects)
0.6 ? 0.5 58.2 ? 1.018/2 14.7 ? 0.676.0 ? 6.316.4 ? 3.36.4 ? 1.3 4.2 ? 0.6
Control group, all subjects (n ?
1.1 ? 0.3 59.0 ? 0.238/415.2 ? 0.465.2 ? 4.3 12.0 ? 1.46.0 ? 0.95.8 ? 0.6
Control group, all MAO-A high
activity (n ? 32 subjects)
0.7 ? 0.459.4 ? ?0.728/4 15.5 ? 0.561.3 ? 5.210.6 ? 1.75.9 ? 0.75.1 ? 0.7
Control group, all MAO-A low
activity (n ? 10 subjects)
2.8 ? 0.658.2 ? 1.0 10/014.7 ? 0.6 76.0 ? 6.316.54 ? 3.36.4 ? 1.36.9 ? ?1.3
MAO-A high activity, all subjects
(n ? 126 subjects)
1.2 ? 0.258.5 ? 0.3 115/1115.0 ? 0.258.9 ? 2.29.2 ? 0.785.1 ? 0.44.6 ? 0.3
MAO-A low activity, all subjects
(n ? 71 subjects)
1.2 ? 0.2 58.4 ? 0.465/6 14.6 ? 0.364.3 ? 3.110.2 ? 1.14.8 ? 0.44.7 ? 0.5
Abbreviations: BDI ? Beck Depression Inventory; ETI ? Early Trauma Inventory; MAO-A ? monoamine oxidase A; NPI-a ? aggression/agitation subscale of
the Neuropsychiatric Inventory; PFC ? prefrontal cortex; PTSD ? posttraumatic stress disorder.
Neurology 76March 22, 2011
Aggression levels were measured with the agitation/aggression
subscale of the Neuropsychiatric Inventory (NPI-a),12a widely used
The NPI is based on a structured interview with a caregiver and
evaluates the severity and frequency of psychopathology along dif-
ferent dimensions. For each dimension, frequency is rated 1–4 and
severity is scored 1–3, while their product represents the total score.
The NPI-a subscale has been used to quantify aggressive behaviors
measure in pharmaceutical intervention studies for aggression con-
trol in patients with TBI.14
Because childhood psychological trauma and a diagnosis of
posttraumatic stress disorder (PTSD) have been shown to poten-
tially impact aggression levels,5,15we evaluated early psychologi-
cal trauma by administering the Early Trauma Inventory (ETI)16
(a validated 56-item interview designed for the assessment of
traumatic experiences in childhood), while current PTSD symp-
tomatology was assessed using the Clinician-Administered
PTSD Scale (CAPS)17,18(a tool designed to assess PTSD symp-
toms according to the DSM-IV-TR).19
Standard protocol approvals, registrations, and patient
consents. All subjects gave informed written consent before
enrollment in the study. The National Naval Medical Center
and the NIH Institutional Review Boards approved all the study
CT imaging and lesion identification. Axial noncontrast
CT scans were acquired and analyzed as described in e-Methods
on the Neurology®Web site at www.neurology.org and in Ray-
mont et al.10PFC territories were identified in each individual
scan as described in e-Methods. Note that if the patient’s lesion
overlapped or partially overlapped with PFC territories, he was
then included in the PFC lesion group; otherwise, he was in-
cluded in the non-PFC lesion group.
Genotyping protocol. Genotyping for the MAO-A VNTR
was performed according to Ducci and collaborators.20Subjects
were divided into 2 subgroups according to the VNTR MAO-A
alleles (MAO-A high-activity group [3.5 and 4 repeats] and
MAO-A low activity group [2, 3, and 5 repeats]) as reported in
the table. The observed high-activity allele/low-activity allele ra-
tio was 1.78, in line with published data.4MAO-A high-activity
and low-activity groups demographic and clinical data were
matched on age (t ? ?0.2; p ? 0.85), education (t ? ?1.0; p ?
0.29), ethnic background (Pearson ?2? 0.3; p ? 0.62), prein-
jury IQ assessed with the AFQT10(t ? 1.4; p ? 0.15), and
depression levels (t ? 0.76; p ? 0.45)11(table).
Lesion maps. First, the relationship between lesion location
and aggressive behavior was explored using a lesion overlap ap-
proach.18Subjects were divided into 2 groups according to
NPI-a scores: a nonaggressive group (n ? 60) showing no patho-
logically aggressive behaviors (NPI-a ? 0) vs an aggressive group
(n ? 58) showing pathologically aggressive behaviors (NPI-a
higher than the PTBI whole group mean: 1.2 ? 1.3). Both
groups were matched on preinjury AFQT percentile score (ag-
gressive vs nonaggressive subjects: 59.9 ? 1.2 vs 62.6 ? 1.3, t ?
1.0, p ? 0.2), age (58.2 ? 0.3 vs 58.4 ? 0.6, t ? 0.4, p ? 0.7),
education (14.8 ? 0.2 vs 14.6 ? 0.3 years, t ? 0.8, p ? 0.6), or
BDI-II scores (10.3 ? 0.9 vs. 8.9 ? 0.4, t ? 1.2, p ? 0.1).
Overlap lesion maps were then generated for both groups; more-
over, subtraction lesion maps were generated to show which ar-
eas were relatively more lesioned in the aggressive compared to
the nonaggressive group and vice versa. To assess the significance
of the prefrontal lesions distribution difference, a ?2test was
applied comparing the frequency of subjects with prefrontal vs
nonprefrontal lesions in the 2 groups.
Analysis of polymorphism/lesion interactions. Second,
the interactions among MAO-A expression, lesion location, and
trauma on aggression levels were explored. A 2 ? 3 analysis of
covariance (ANCOVA) on NPI-a scores was conducted with
genotype (MAO-A high-activity, MAO-A low-activity) and
group (PFC lesion, non-PFC lesion, control) as between-
subjects factors and ETI scores and PTSD symptomatology as
covariates. In a planned secondary analysis, t tests were then used
to explore differences on NPI-a aggression scores between carri-
ers of MAO-A high-activity and MAO-A low-activity alleles sep-
arately for each group (PFC, non-PFC, control). These analyses
were performed using NPI-a scores adjusted for the ANCOVA
covariates (NPI-a least square means).
Traumatic experiences and aggression. Third, the effects
of PTBI and MAO-A expression on the relationship between
aggressive behavior and early traumatic experiences as well as
PTSD were explored. Spearman correlations were used to corre-
late NPI-a scores with ETI and PTSD symptoms separately for
the 3 lesion groups (PFC, non-PFC, control).
Lesion volume and aggression. Finally, using Spearman
correlations the percentage of PFC volume loss due to lesion was
correlated with NPI-a scores separately for MAO-A high and
MAO-A low allele carriers in the PFC and non-PFC groups. The
subgroups were matched in volume loss (PFC: 3.4% ? 0.3 vs
3.6% ? 0.6, p ? 0.61; non-PFC: 2.4% ? 0.3 vs 2.7% ? 0.5,
p ? 0.61).
Significance level for all analyses was set at p ? 0.05 (2-
tailed). All results are reported as means ? standard errors.
RESULTS Lesion maps. Lesionmapsoftheaggressive
and nonaggressive groups are shown in figure 1. Sub-
traction lesion maps showing those brain regions that
were more likely to contain a lesion in the aggressive
group compared to the nonaggressive group and vice
versa are shown in figure 2. Note the more focal in-
volvement of PFC areas in the aggressive group com-
pared to a more widespread lesion pattern in the
nonaggressive group. In the aggressive group (58 sub-
jects), 46 subjects presented with PFC lesions and 12
subjects presented with non-PFC lesions while in the
nonaggressive group (60 subjects) 28 subjects presented
with PFC lesions and 32 subjects presented with non-
more represented in the aggressive compared to the
nonaggressive group (p ? 0.001).
Analysis of polymorphism/lesion interactions. Sec-
ond, the interactions among MAO-A expression, le-
sion location, and trauma on aggression were
explored. The 2 ? 3 ANCOVA on NPI-a scores
revealed no main effects for genotype (F1,184? 0.5;
p ? 0.46) and group (F2,184? 0.2; p ? 0.85), but an
interaction effect for genotype ? group (F2,184?
5.4; p ? 0.005) and an effect for both the covariates
studied, i.e., the ETI score (F1,184? 6.5; p ? 0.01)
and number of PTSD symptoms (F1,184? 7.4; p ?
Neurology 76 March 22, 2011
0.007). All the other interactions were not signifi-
cant. The planned follow-up analyses revealed lower
NPI-a scores for the MAO-A high-activity compared
to the MAO-A low-activity allele carriers in the con-
trol group (MAO-A high vs MAO-A low least
squares means: 0.5 ? 0.1 vs 2.4 ? 0.5, t ? 3.3; p ?
0.005). Although MAO-A activity did not modulate
aggression levels in patients with PFC lesions
(MAO-A high vs MAO-A low least squares means:
1.1 ? 0.3 vs 1.2 ? 0.3; p ? 0.967), higher NPI-a
scores for MAO-A high activity compared to the
MAO-A low activity carriers were found in patients
with non-PFC lesions (MAO-A high vs MAO-A low
least squares means: 2.1 ? 0.2 vs 0.6 ? 0.2, t ? 3.0;
p ? 0.007). Raw NPI-a scores divided according to
MAO-A activity and lesion location are reported in
the table. Least squares means according to MAO-A
activity and lesion location are reported in figure 3.
Traumatic experiences and aggression. Third, the ef-
fects of PTBI and MAO-A expression on the rela-
tionship between aggressive behavior and early
traumatic experiences as well as PTSD were ex-
plored. Statistics for early traumatic experiences (ETI
scores) and PTSD (CAPS scores) are reported in the
table. Analyzing separately the PFC, non-PFC, and
control groups, we showed positive correlations be-
tween NPI-a and ETI and CAPS scores only for the
control group (ETI: rho ? 0.35, p ? 0.02; PTSD:
rho ? 0.30, p ? 0.02) and non-PFC lesion group
(ETI: rho ? 0.28, p ? 0.04; PTSD: rho ? 0.43, p ?
0.01) while we did not find any correlation between
NPI-a and ETI and CAPS scores in the PFC lesion
group (ETI: rho ? 0.1, p ? 0.15; PTSD: rho ?
0.09, p ? 0.15).
Lesion volume and aggression. Finally, we found a
positive correlation between volume loss and NPI-a
scores in MAO-A high carriers of the non-PFC
group (rho ? 0.52, p ? 0.002) while NPI-a scores
did not correlate with volume loss in all the other
subgroups (non-PFC: MAO-A low [rho ? 0.2, p ?
Figure 1 Lesion overlap map for the aggressive (A, red areas) and nonaggressive subjects (B, blue areas)
Results are overlaid on Montreal Neurological Institute T1 brain standard template. Images in radiologic convention (left side of the brain is represented on
the right side of the pictures).
Neurology 76March 22, 2011
0.6]; PFC: MAO-A high [rho ? 0.1, p ? 0.5];
MAO-A low [rho ? 0.2, p ? 0.4]).
DISCUSSION The goals of this study were to exam-
ine 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 activ-
ity on the relationship between psychological trauma
and PTBI-related aggression. First, we demonstrated
that PFC lesions are overrepresented in aggressive pa-
tients with PTBI compared to nonaggressive subjects
with PTBI. Second, we showed an interaction be-
tween 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 con-
trol group, the reverse effect was found in the non-
PFC group, and no effect was found in the PFC
Figure 2Lesion subtraction map between the aggressive and nonaggressive subjects
Red blobs represent those areas relatively more lesioned in the aggressive than in the nonaggressive group while the blue blobs represent those areas
relatively more lesioned in the nonaggressive than in the aggressive group. Results are overlaid on Montreal Neurological Institute T1 brain standard
template. Images in radiologic convention (left side of the brain is represented on the right side of the pictures). A greater likelihood of brain damage in
prefrontal areas (especially ventral, medial, and frontopolar regions) can be seen for the aggressive vs nonaggressive group subtraction map.
Figure 3Least squares means aggression/agitation subscale of the Neuropsychiatric Inventory (NPI-a) scores (mean ? SEM) corrected for
Early Trauma Inventory scores and posttraumatic stress disorder symptoms for all experimental subjects divided according to
monoamine oxidase A activity and lesion location
(A) Prefrontal cortex (PFC) lesion group; (B) non-PFC lesion group; (C) controls.
Neurology 76March 22, 2011
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.5,6,9,21Absence of
MAO-A activity has been shown to be related with
aggressive antisocial behaviors in a Dutch kindred
showing a MAO-A null point mutation6and in
MAO-A knockout animal models.21Moreover, a
seminal study of Caspi and collaborators5showed 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
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.7,8,22-25In healthy controls, functional neuro-
imaging studies showed both a reduction of ventral
PFC activity during mental imagery of violent acts8,22
and an increase of ventral PFC activity during inhibi-
tion of impulsive behaviors.23Moreover, focal brain
lesion studies revealed a relationship between ventral
PFC structural alterations and verbal aggression in
subjects with PTBI.7However, while ventromedial
PFC is thought to play a pivotal role in aggression,
other PFC regions including ventrolateral PFC and
cingulate cortex24,25are 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 ag-
gressive behavior. MAO-A alleles that alter expres-
sion levels have been shown to impact prefrontal
structural and functional anatomy in previous neuro-
imaging studies.23,25For example, during an emo-
tional arousal task, carriers of MAO-A low-activity
alleles showed reduced orbitofrontal activity com-
pared to subjects with high-activity alleles.25Reduced
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 ac-
tivity have been associated with reduced MAO-A ac-
tivity, 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 pre-
Consistent with this observation, we also showed
both a significant correlation between aggression and
early traumatic experiences and PTSD in those sub-
jects 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,26while retrieval of traumatic childhood mem-
ories has been linked to reduced activations of or-
bitofrontal and medial frontal territories in subjects
with borderline personality disorder.27These 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 behav-
iors 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,29attention-deficit/
hyperactivity disorder,30antisocial conduct,31,32and
childhood externalizing behaviors.28Although to
date the neurobiological basis of these conditions is
not completely understood, they can be collectively
characterized as impulsivity and behavioral dyscon-
trol problems. Consistent with our results, the rela-
tionship 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.23In that study, the presence of
the high-activity MAO-A allele correlated with re-
duced activation in posterior cortices, thus suggest-
ing an effect of the MAO-A high-activity allele on
posterior cortical functional anatomy.23In 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
Neurology 76March 22, 2011
high allele23and lesion presence in the posterior cor-
tex 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 as-
sociated with higher NPI-a scores in MAO-A high-
activity allele carriers. However, further studies are
needed to better clarify the effects of posterior corti-
ces 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 litera-
ture suggest that several factors including genetic
polymorphisms and brain damage may modulate ag-
gressive behaviors via altered cognitive and social
processes mediated by the PFC. However, we also
showed that aggression levels in subjects with pre-
frontal 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 physi-
cal aggression and bodily injuries. While this com-
homogeneous regarding previous exposure to aggres-
sion, studies on subjects without war-related experi-
ences are needed to validate these findings in the
Moreover, given the multifaceted nature of ag-
gression, 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 indi-
viduals 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 ag-
gressive behavior in patients with prefrontal or poste-
rior lesions and 2) other factors ranging from the
severity and frequency of previous traumatic experi-
ences to genetic polymorphisms need to be taken
into consideration when determining the effects of
brain damage on aggression. Future studies are
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.
The authors thank the Vietnam veterans who participated in this study.
Without their long-term commitment to improving the health care of
veterans, this study could not have been completed. The authors thank
the National Naval Medical Center for their support and provision of
their facilities and S. Bonifant, B. Cheon, C. Ngo, A. Greathouse, K.
Reding, and G. Tasick for their help with the testing of participants and
organization of this study.
Dr. Pardini and Dr. Krueger report no disclosures. Dr. Hodgkinson re-
ceives intramural research support from the NIH. Dr. Raymont and C.
Ferrier report no disclosures. Dr. Goldman serves on the editorial boards
of Biological Psychiatry and Addictions Biology. Dr. Strenziok and Dr.
Guida report no disclosures. Dr. Grafman serves as Co-editor of Cortex
and receives research support from the Intramural Research Program
NIH/NINDS and the Henry M. Jackson Foundation.
Received May 28, 2010. Accepted in final form November 9, 2010.
1. Tateno A, Jorge RE, Robinson RG. Clinical correlates of
aggressive behavior after traumatic brain injury. J Neuro-
psychiatry Clin Neurosci 2003;15:155–160.
2. Nelson RJ, Trainor BC. Neural mechanisms of aggression.
Nat Rev Neurosci 2007;8:536–546.
3. Shih JC, Chen K, Ridd MJ. Monoamine oxidase: from
genes to behavior. Annu Rev Neurosci 1999;22:197–217.
4.Sabol SZ, Hu S, Hamer D. A functional polymorphism in
the monoamine oxidase A gene promoter. Hum Genet
5.Caspi A, McClay J, Moffitt TE, et al. Role of genotype in
the cycle of violence in maltreated children. Science 2002;
6.Brunner HG, Nelen M, Breakefield XO, Ropers HH, van
Oost BA. Abnormal behavior associated with a point mu-
tation in the structural gene for monoamine oxidase A.
7.Grafman J, Schwab K, Warden D, Pridgen A, Brown HR,
Salazar AM. Frontal lobe injuries, violence, and aggression:
a report of the Vietnam Head Injury Study. Neurology
8. Pietrini P, Guazzelli M, Basso G, Jaffe K, Grafman J. Neu-
ral correlates of imaginal aggressive behavior assessed by
positron emission tomography in healthy subjects. Am J
9. Siever LJ. Neurobiology of aggression and violence. Am J
10.Raymont V, Greathouse A, Reding K, Lipsky R, Salazar A,
Grafman J. Demographic, structural and genetic predic-
tors of late cognitive decline after penetrating head injury.
11.Beck AT, Steer RA, Ball R, Ranieri W. Comparison of
Beck Depression Inventories IA and II in psychiatric out-
patients. J Pers Assess 1996;67:588–597.
12. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S,
Carusi DA, Gornbein J. The Neuropsychiatric Inventory:
comprehensive assessment of psychopathology in demen-
tia. Neurology 1994;44:2308–2314.
13.Pritchard AL, Ratcliffe L, Sorour E, et al. Investigation of
dopamine receptors in susceptibility to behavioural and
Neurology 76 March 22, 2011
psychological symptoms in Alzheimer’s disease. Int J Geri-
atr Psychiatry 2009;24:1020–1025.
Masanic CA, Bayley MT, VanReekum R, Simard M.
Open-label study of donepezil in traumatic brain injury.
Arch Phys Med Rehabil 2001;82:896–901.
Jakupcak M, Conybeare D, Phelps L, et al. Anger, hostil-
ity, and aggression among Iraq and Afghanistan War veter-
ans reporting PTSD and subthreshold PTSD. J Trauma
Bremner JD, Vermetten E, Mazure CM. Development
and preliminary psychometric properties of an instrument
for the measurement of childhood trauma: the Early
Trauma Inventory. Depress Anxiety 2000;12:1–12.
Blake DD, Weathers FW, Nagy LM, et al. The develop-
ment of a Clinician-Administered PTSD Scale. J Trauma
Koenigs M, Huey ED, Raymont V, et al. Focal brain dam-
age protects against post-traumatic stress disorder in com-
bat veterans. Nat Neurosci 2008;11:232–237.
American Psychiatric Association. Diagnostic and Statisti-
cal Manual of Mental Disorders, fourth edition, text revi-
sion. Washington, DC: American Psychiatric Association;
Ducci F, Enoch MA, Hodgkinson C, et al. Interaction
between a functional MAOA locus and childhood sexual
abuse predicts alcoholism and antisocial personality disor-
der in adult women. Mol Psychiatry 2008;13:334–347.
Cases O, Seif I, Grimsby J, et al. Aggressive behavior and
altered amounts of brain serotonin and norepinephrine in
mice lacking MAOA. Science 1995;268:1763–1766.
Strenziok M, Krueger F, Heinecke A, et al. Developmental
effects of aggressive behavior in male adolescents assessed
with structural and functional brain imaging. Soc Cogn
Affect Neurosci Epub 2009 Sep 21.
Passamonti L, Fera F, Magariello A, et al. Monoamine
oxidase-a genetic variations influence brain activity associ-
ated with inhibitory control: new insight into the neural
correlates of impulsivity. Biol Psychiatry 2006;59:334–
Raine A, Buchsbaum MS, Stanley J, Lottenberg S, Abel L,
Stoddard J. Selective reductions in prefrontal glucose me-
tabolism in murderers. Biol Psychiatry 1994;36:365–373.
Meyer-Lindenberg A, Buckholtz JW, Kolachana B, et al.
Neural mechanisms of genetic risk for impulsivity and vio-
lence in humans. Proc Natl Acad Sci USA 2006;103:
Andersen SL, Tomada A, Vincow ES, Valente E, Polcari
A, Teicher MH. Preliminary evidence for sensitive periods
in the effect of childhood sexual abuse on regional brain
development. J Neuropsychiatry Clin Neurosci 2008;20:
Schmahl CG, Vermetten E, Elzinga BM, Bremner JD. A
positron emission tomography study of memories of child-
hood abuse in borderline personality disorder. Biol Psychi-
Kim-Cohen J, Caspi A, Taylor A, et al. MAOA, maltreat-
ment, and gene-environment interaction predicting chil-
dren’s mental health: new evidence and a meta-analysis.
Mol Psychiatry 2006;11:903–913.
Ni X, Sicard T, Bulgin N, et al. Monoamine oxidase a gene
is associated with borderline personality disorder. Psychiatr
Manor I, Tyano S, Mel E, et al. Family-based and associa-
tion studies of monoamine oxidase A and attention deficit
hyperactivity disorder (ADHD): preferential transmission
of the long promoter-region repeat and its association with
impaired performance on a continuous performance test
(TOVA). Mol Psychiatry 2002;7:626–632.
Vollm BA, Zhao L, Richardson P, et al. A voxel-based
morphometric MRI study in men with borderline person-
ality disorder: preliminary findings. Crim Behav Ment
Raine A, Buchsbaum M, LaCasse L. Brain abnormalities in
murderers indicated by positron emission tomography.
Biol Psychiatry 1997;42:495–508.
MOC PIP. . .what?
We’re here to help you make sense of it all.
If this acronym doesn’t make sense to you, it will. Because now is the time to start preparing to meet
the requirements of the four components of the ABMS-mandated Maintenance of Certification
(MOC) program: Professional Standing, Self-Assessment and Lifelong Learning, Cognitive Exper-
tise—and the new Performance in Practice (PIP), which can take up to two years to complete.
Make sense of it. Visit www.aan.com/view/mocpip.
Neurology 76March 22, 2011