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Blunted Prefrontal Cortical 18Fluorodeoxyglucose Positron Emission Tomography Response to Meta-Chlorophenylpiperazine in Impulsive Aggression
Antonia S. New, MD;
Erin A. Hazlett, PhD;
Monte S. Buchsbaum, MD;
Marianne Goodman, MD;
Diedre Reynolds, MD;
Vivian Mitropoulou, MA;
Larry Sprung, BA;
Robert B. Shaw, Jr, BS;
Harold Koenigsberg, MD;
Jimcy Platholi, MA;
Jeremy Silverman, PhD;
Larry J. Siever, MD
Arch Gen Psychiatry. 2002;59:621-629.
ABSTRACT
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Background Impulsive aggression is a prevalent problem and yet little is known
about its neurobiology. Preclinical and human studies suggest that the orbital
frontal cortex and anterior cingulate cortex play an inhibitory role in the
regulation of aggression.
Methods Using positron emission tomography, regional metabolic activity in response
to a serotonergic stimulus, meta-chlorophenylpiperazine (m-CPP), was examined
in 13 subjects with impulsive aggression and 13 normal controls. The anterior
cingulate and medial orbitofrontal regions were hypothesized to respond differentially
to m-CPP in patients and controls. In the frontal cortex, regional metabolic
glucose response to m-CPP was entered into a group (impulsive aggressive,
control) x slice (dorsal, middle, orbital) x position (medial,
lateral) x location (anterior, posterior) x hemisphere (right,
left) mixed-factorial analysis of variance design. A separate group (impulsive
aggressive, controls) x anteroposterior location (Brodmann areas 25,
24, 31, 29) x hemisphere (right, left) analysis of variance was used
to examine regional glucose metabolism in the cingulate gyrus.
Results Unlike normal subjects, patients with impulsive aggression did not show
activation specifically in the left anteromedial orbital cortex in response
to m-CPP. The anterior cingulate, normally activated by m-CPP, was deactivated
in patients; in contrast, the posterior cingulate gyrus was activated in patients
and deactivated in controls.
Conclusions The decreased activation of inhibitory regions in patients with impulsive
aggression in response to a serotonergic stimulus may contribute to their
difficulty in modulating aggressive impulses.
INTRODUCTION
ALTHOUGH VIOLENT crime has decreased in the past decade, violent incidents
involving impulsive aggression rather than planned violence are increasing.1 These include juvenile violence, domestic violence,
and workplace acts of aggression.2-3
Violence and homicide are significantly associated with mental illness, especially
antisocial and borderline personality disorder.4
Considering the serious consequences of impulsive-aggressive behavior, its
neurobiology has received little scrutiny.
Evidence from metabolite and neuroendocrine studies has linked abnormalities
in central serotonin activity to impulsive aggression.5-8
The association of lesions in the orbitofrontal cortex (OFC) and anterior
cingulate gyrus (ACG) with disinhibited aggression suggests that faulty regulation
of negative emotion, through a reduced serotonin-mediated activation of the
prefrontal cortex, may predispose an individual to impulsive aggression.9
BRAIN REGIONS AND AGGRESSION
Studies of brain lesions suggest regional control of aggression, with
the ACG and OFC playing central roles.10-15
The critical influence of the OFC and the ACG in human aggression is exemplified
by the case of Phineas Gage, who, after a penetrating brain injury, became
hostile and verbally aggressive. Computerized reconstruction of Gage's skull
demonstrated the location of his brain lesion in the anteromedial cortex,
the OFC and the ACG, with more marked damage in the left hemisphere.16
Most lesions in the medial OFC also include damage to the ACG. In the
human brain, the ACG has 2 main subdivisions: the dorsal cognitive division
(including the dorsal part of Brodmann areas [BAs] BA24 and BA32) and the
rostral-ventral affective division (including the rostral part of BA24, BA32,
and BA25).17-18 The affective
subdivision receives wide input from regions, including the hippocampus, amygdala,
medial OFC, and dorsal raphe, and projects to the basal ganglia, subthalamic
nuclei, and lateral hippocampus.18-19
In an animal model, electrical stimulation of the ACG in the cat brain ACG
resulted in an increased latency in attack behavior.20
While the ACG is implicated in affective-cognitive activity,18 the posterior cingulate gyrus is implicated in sensory
processing and perhaps in processing fear-inducing stimuli.21-25
The posterior cingulate has reciprocal pathways to the hippocampus, ACG, parahippocampal
gyrus, and temporal areas.26-27
POSITRON EMISSION TOMOGRAPHY STUDIES AND AGGRESSION
Positron emission tomography (PET) studies of relative glucose metabolic
rate (rGMR) have related abnormalities in the ACG and prefrontal cortex to
impulsive aggression.28-30
In an anger-induction model, normal men showed increased rGMR in the left
OFC and right ACG,31 perhaps reflecting the
normal activation of inhibitory regions in response to anger stimulation.
A variety of serotonergic agents can modulate rGMR in the prefrontal
cortex and in the ACG. d-Fenfluramine has been found to increase rGMR in the
left ACG and in the prefrontal cortex in normal subjects.32
In our previous study, normal subjects showed increased metabolism in the
ACG and OFC following fenfluramine administration, while patients did not.33 These findings were replicated in a study of borderline
personality disorder.34 Meta-chlorophenylpiperazine
(m-CPP), a nonspecific 5-HT agonist,35-36
increased rGMR in the right OFC, middle frontal gyrus, posterior cingulate,
and thalamus in normal subjects.37
Our study assesses rGMR in a larger sample of patients with impulsive
aggression and normal controls after administration of m-CPP. We hypothesized
that (1) patients would show decreased rGMR in the OFC and ACG after m-CPP
relative to controls; (2) the posterior cingulate would not show blunting
in patients vs controls; (3) in patients, medial regions of the OFC would
show a more blunted response to m-CPP than would lateral regions, suggesting
that the ACG with the adjacent OFC, which normally modulates aggression through
a serotonergic mechanism, is underactive in impulsive aggression.
SUBJECTS AND METHODS
SUBJECTS
Thirteen patients with impulsive aggression (8 men, 5 women; mean [SD]
age, 31.7 [8.5] years; range, 20-43 years; 9 right-handed, 3 left-handed,
1 mixed) who met DSM-IV criteria for 1 or more personality
disorders were included. Patients with a history of schizophrenia, psychotic
disorder, or bipolar type I affective disorder were excluded. Patients with
current major depressive disorder were also excluded since this has been associated
with impaired brain regional response to fenfluramine.38
All patients had been medication-free for 6 weeks or more (9 of 13 had never
taken medication). An age- and sex-matched group of 13 normal subjects was
also studied (8 men,5 women; mean [SD] age, 31.6 [8.1] years; range, 21-43
years; 11 right-handed, 1 left-handed, 1 mixed).
Subjects were screened for severe medical or neurological illness, head
injury, history of alcohol/drug dependence, and substance abuse in the past
6 months. All subjects had negative urine toxicology screen results for drugs
of abuse, and women had negative pregnancy tests on each positron emission
tomography (PET) scan day. Participants provided written informed consent
in accordance with the guidelines of our institutional review board. Patients
were recruited for the study through advertisement in local newspapers (90%)
and through referrals from outpatient psychiatric clinics at the Bronx Veterans
Affairs Medical Center (Bronx, NY) and Mount Sinai School of Medicine (New
York, NY) (10%). Of 85 subjects screened, 13 subjects were successfully recruited
into the patient group. Patients were excluded, in order of frequency, because
of current substance abuse, a chronic medical problem such as diabetes or
heart disease, pregnancy, the presence of current major depression, and in
one case, the presence of current psychotic symptoms. In addition, one subject
declined participation because of fear of the radioactive isotope. In the
control group, approximately 90 candidates responded to our advertisement.
Many subjects were excluded because of the presence of an Axis I or Axis II
diagnosis in themselves (detected at screening) or a first-degree relative.
Axis I and personality disorder diagnoses were made through interviews
with a psychologist using the Structured Clinical Interview for DSM-IV Axis I disorders39 and the Structured
Interview for DSM-IV Personality Disorders (SIDP-IV),40 respectively. Trait aggression was assessed using
the Module for Intermittent Explosive Disorder–Revised (IED-R)41 and depression with the Hamilton Depression Rating
Scale (HDRS).42 All subjects completed the
Buss-Durkee Hostility Inventory (BDHI)43; both
total (BDHItotal) and composite Irritability-Assaultiveness subscale
(BDHIIRR-ASS) scores have been associated with biological markers
of aggression7 (Table 1).
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Table 1. Impulsive-Aggressive Patients With Personality Disorders*
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All patients met the following criteria: (1) significant physical and/or
verbal aggression meeting criteria for IED-R ( = 0.92); (2) impulsivity
as assessed by the SIDP-IV "impulsiveness" criterion for borderline personality
disorder ( = 0.78), including behavior such as reckless driving or
impulsive sexual behavior; and/or (3) self-damaging acts (predominantly self-mutilatory
cutting of the skin) as assessed by the SIDP-IV "self-damaging" borderline
criterion (A5) (interrater reliability, = 0.90). Controls met none
of the 3 above-defined criteria and had no personal or first-degree family
history of psychiatric illness.
Prolactin and cortisol levels, obtained from all subjects except for
2 controls (technical difficulties with the intravenous line precluded blood
sampling), were measured as described previously, and the peak minus baseline
was calculated ( prolactin, cortisol).44
PROCEDURE
On 2 separate occasions, each participant received m-CPP or placebo
(counterbalanced to control for order effects). At 8 AM, after an overnight
fast, 1 intravenous line was inserted into each forearm (1 used for blood
sampling, the other for injection of m-CPP/placebo and 18fluorodeoxyglucose).
An 0.08-mg/kg solution of m-CPP/placebo in an identical syringe of 20 mL of
saline was given by slow push over 90 seconds. Immediately following, 5 mCi
(185 MBq) of 18fluorodeoxyglucose was administered into the venous
set rubber diaphragm behind the subject's back as a 4560-second slow push.
The subject remained in a resting state in a sound-attenuated, dimly lit room
for the 35-minute tracer-uptake period, after which the subject was escorted
to an adjacent bathroom to void. The subject was then positioned in the PET
scanner using a previously prepared thermosetting plastic mask. The imaging
data-acquisition period lasted about 40 minutes. Scans were separated by at
least 1 week to allow for drug elimination (3-4 days) and to coincide with
a weekly scan schedule. All subjects and staff were blind to the dosing/placebo
regimen. On each scan day, patients were evaluated with the HDRS.
IMAGING
Positron emission tomography scans were carried out as described elsewhere33, 45 (General Electric Medical Systems
scanner model 2048, General Electric, Milwaukee, Wis; [resolution 4.5 mm in
plane, 5.0 mm axially]). Fifteen slices at 6.5-mm intervals were obtained
in 2 sets to cover the entire brain. Slice counts of 1.53 million counts are
typical. Scans were reconstructed with a blank and a transmission scan using
the Hanning filter (width, 3.15 mm). The same individually molded thermoplastic
face mask was used for each scan to keep the head stationary during image
acquisition and to assist in PET/magnetic resonance imaging (MRI) image coregistration.
Positron emission tomography images were obtained in nCi/pixel and standardized
as relative metabolic rate (rGMR) by dividing each pixel by the mean value
for the entire brain (defined by brain edge from coregistered MRI). While
this limits interpretations of single-structure absolute activity, this method
is widely used when evaluating hypotheses related to patterns of metabolic
rate across brain areas and was used in 4 earlier imaging studies of serotonin
activation.33-34,37-38
Within 1 week of their PET scans, participants underwent MRI examination as
described previously46 (General Electric Signa
5X, acquisition parameters: repetition time, 24 milliseconds; echo time, 5
milliseconds; flip angle, 40°; slice thickness, 1.2 mm; matrix, 256 x
256; field of view, 23 cm). Magnetic resonance images were resectioned to
standard Talairach-Tournoux47 position. Positron
emission tomography–MRI coregistration used the algorithm of Woods et
al.48 Brain edges were visually traced on all
MRI axial slices. Intertracer reliability on 27 individuals is 0.99 for area.
On the basis of earlier studies,33-34,37
the cingulate, orbitofrontal, and medial frontal regions were hypothesized
to respond differentially to serotonin agonists in patients and controls.
These areas were located in advance of any analysis in the Talairach-Tournoux
atlas and their coordinates recorded (Table
2). For the cingulate, we used x-coordinates 5 mm from midline;
for BAs, we chose the position of numerals or halfway between duplicate numerals,
5 mm from the cortical edge. The square region of interest (ROI) (5 x
5 pixels) was applied centered on that coordinate and at the proportion as
the brain-bounding box in the Talairach-Tournoux atlas. An adjustment was
made so that ROIs were moved closer to the centroid of the slice if the box
fell partly outside the coregistered brain outline, as could happen in brains
that were especially narrow in the y direction for boxes placed at 45°
and 135°.
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Table 2. Talairach Coordinates for Locatization
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This method, the reverse Talairach hypothesis–driven strategy,
was used for 3 reasons: (1) to minimize type I statistical errors in evaluating
large numbers of ROIs in both hemispheres through the use of multiway repeated-measures
analysis of variance (ANOVA) and a single F ratio test indicating the hypothesized
diagnostic group x condition x region interaction; (2) to minimize
type II errors resulting from assessing small individual, potentially noisy
ROIs and failing to observe orbitofrontal system–wide response by combining
ROIs; and (3) to provide standard and known brain atlas locations for replication.
We also controlled type I error by not discussing main effects or interactions
that are not interpretable (eg, main effect of slice level across structures
measured at multiple axial slice levels) or peripheral to our interest (main
effect of hemisphere across the normal controls and patients). Our analysis
is limited in power by the sample size (n = 13 in each of the 2 groups).
STATISTICAL DESIGN
A 2 x 3 x 2 x 2 x 2 mixed-factorial ANOVA design
was applied to rGMR data obtained from frontal ROIs. Dependent variables were
expressed as difference scores (m-CPP - placebo) for rGMR within each
ROI. The first variable consisted of the 2 participant groups (impulsive-aggressive
and controls), and the remaining variables were all repeated measures, consisting
of 3 slice levels (dorsal, middle, and orbital; corresponding to Talairach-Tournoux
levels: +12, +4, and -4, respectively), 2 medial/lateral positions (medial
and lateral prefrontal cortex), 2 anteroposterior locations (anterior and
posterior), and 2 hemispheres (right and left). At the dorsal slice level
(+12 slice), the medial regions included BA10 (anterior region) and BA32 (posterior
region), and the lateral regions included BA46 (anterior region) and BA45
(posterior region). At the middle and orbital slice levels, the ROIs were
the same as at the dorsal level except that the lateral regions were BA10
(anterior region) and BA47 (posterior region).
A separate ANOVA was performed on 4 BAs within the cingulate gyrus.
This 2 x 4 x 2 mixed-factorial design was employed to examine
the drug-placebo rGMR difference values within the BAs for the 2 cohorts.
The first variable consisted of the 2 groups, the second variable consisted
of 4 BAs in the anteroposterior position (BA25, BA24, BA31, and BA29), and
the third variable consisted of 2 hemispheres. Brodmann area 25 was located
on the +4 slice level and the 3 remaining cingulate regions were located on
the +12 slice level. All statistical analyses involving repeated measures
with more than 2 levels used Greenhouse-Geisser  corrections to adjust
probabilities for repeated-measures F values. Uncorrected degrees of freedom
are reported. To detect the source of significant interactions between group
and hypothesized BA, we carried out an ANOVA on each BA separately. For interactions
involving slice level, replicated ROIs adjacent in position or hemisphere
were not followed up because they were not part of our hypothesis or were
neuroanatomically not important. In addition, we report results of the Mauchley
sphericity test, the Levine homogeneity of variance test, and the multivariate
Rao R.
To explore relationships between the prefrontal cortex and cingulate
gyrus rGMR and clinical measures of the degree of impulsivity, measured by
BDHItotal and BDHIIRR-ASSscores, Spearman correlations
were computed only for regions entered into the ANOVAs above.
EXPLORATORY SIGNIFICANCE PROBABILITY MAPPING
To provide a survey of the entire brain slice, we carried out voxel-by-voxel t tests on the same brain slices assessed by the stereotaxic
ROI method. The significance probability mapping technique is similar to other
approaches but uses MRI-based region alignment.49
Continuous edges were manually drawn around the brain. Nine midline points
equally spaced in the z direction were identified. Slices were then adjusted
by the number of rows and columns so that every slice contained an equal number
of pixels, with every edge pixel aligned and midline pixels positioned in
a vertical strip at the edge center. Positron emission tomography images for
the placebo and drug scans were coregistered to the same MRI similarly standardized,
and unpaired t tests were carried out for the drug
minus placebo difference scores. To confirm our original report of blunted
response to fenfluramine and to provide validation of the reverse-Talairach
ROI approach, we present these images with 1-tailed probability maps. To examine
other already published studies and provide exploratory results for future
investigators, we present 2-tailed probability maps.
RESULTS
NEUROENDOCRINE MEASURES
Analysis of mean responses to m-CPP showed no significant between-group
differences for either prolactin levels (controls: mean [SD], 20.22
[21.34] ng/mL; median, 18.1 ng/mL; patients: 23.55 [18.78] ng/mL; median,
16.3 ng/mL; t22 = 0.41, P = .69; Mann-Whitney U = 63.5, P = .64) or
cortisol levels (controls: 11.45 [7.60] µg/dL; median, 12.5 µg/dL;
patients: 12.97 [6.08] µg/dL; median, 13.3 µg/dL; t22
= -0.54, P = .59; Mann-Whitney U = 58, P = .46).
CLINICAL MEASURES
The mean (SD) HDRS score of patients on the day of m-CPP administration
was 10.5 (4.8), a typical score for patients with personality disorders who
experience some dysphoria even when not clinically depressed. As expected,
BDHI scores showed significant between-group differences (BDHItotal,
controls: mean [SD], 20.23 [7.84]; range, 6-32; median, 22.0; patients: 40.54
[11.74]; range, 14-49; median, 46.0; t24 = 5.18, P<.001; Mann-Whitney U = 17.5, P<.001; BDHIIRR-ASS, controls: mean, 5.93 [3.86]; range,
1-15; median, 6.0; patients: 13.54 [4.52]; range, 2-18; median, 14.0; t24 = 4.62, P<.001; Mann-Whitney U = 17.5, P<.001).
POSITRON EMISSION TOMOGRAPHY
Prefrontal Cortex
Effects of m-CPP.
Figure 1 shows mean rGMR difference
scores (m-CPP - placebo) in frontal lobe ROIs for patients and controls.
A 2 (group) x 3 (slice) x 2 (medial/lateral cortex) x 2
(anterior, posterior location) x 2 (hemisphere) ANOVA of rGMR difference
scores revealed a significant group x slice x medial/lateral x
hemisphere interaction (univariate: F2,48 = 5.20, P = .009; multivariate:
Rao R2,23 = 4.54, P = .02). In the right hemisphere, patients
showed a blunted m-CPP response at the orbital slice level in the lateral
but not medial frontal regions compared with controls. In the left hemisphere,
this effect was reversed, with patients, unlike controls, showing a blunted
response at the orbital slice level in medial but not lateral frontal regions.
Although the interaction effect was statistically significant, simple-effects
tests for each of the regions within the ANOVA failed to reach significance.
The main effect of group (F1,24 = 0.04, P
= .83) and all other interpretable interaction effects with group (group x
medial/lateral; F2,48 = 0.08, P = .91;
group x right/left; F1,24 = 0.40, P
= .53) failed to reach significance. Despite the fact that none of the post-hoc
tests were significant, this interaction reflects a significant rGMR pattern
that differs between the 2 groups.
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Figure 1. Frontal cortex regions. Mean relative
glucose metabolic rate (rGMR) difference values (meta-chlorophenylpiperazine
[m-CPP]- placebo) in prefrontal cortex regions of interest are shown
for normal controls and patients with impulsive aggression (group x
slice x medial/lateral x hemisphere interaction; F2,48
= 5.20, P = .009). At the most dorsal slice level (+12), the
medial regions include BA10 and BA32 and the lateral regions include BA46
and BA45. For the middle (+4) and orbital (-4) slice levels, the medial
regions include BA10 and BA32 and the lateral regions include BA10 and BA47.
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Baseline.
To determine whether the groups differed in baseline rGMR, we conducted
a 2 (group) x 3 (slice) x 2 (medial/lateral cortex) x 2
(anterior and posterior) x 2 (hemisphere) ANOVA on the placebo scan
data. There was neither a main effect of group nor an interaction effect,
indicating that patients did not differ from controls in baseline rGMR in
the frontal lobe ROIs examined.
Cingulate Gyrus
Effects of m-CPP.
Figure 2 shows mean rGMR difference
scores (m-CPP - placebo) in the cingulate gyrus for patients and controls.
A 2 (group) x 4 (anteroposterior BA) x 2 (hemisphere) ANOVA revealed
a significant group x anteroposterior region interaction (univariate
F3,72 = 7.12, P<.001;
multivariate Rao R3,22 = 4.63, P = .01),
indicating that in the ACG (BA25), m-CPP response was blunted in patients compared with controls.
The Levene test for homogeneity of variances (ANOVA on absolute within-cell
deviation scores, degrees of freedom for all F values 1,24) shows none of
the 8 variables to be significant (P range, .2-.97)
(Rao R3,22 = 7.11, P = .002 [Wilks  , 0.507]; Mauchley sphericity test Wilks
= 0.32;  25 = 25.8, P<.001).
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Figure 2. Cingulate gyrus regions (meta-chlorophenylpiperazine
[m-CPP] effect). Mean relative glucose metabolic rate (rGMR) difference values
(m-CPP - placebo) in the cingulate gyrus are shown for normal controls
and patients with impulsive aggression (group x anteroposterior cingulate
region interaction; F3,72 = 7.12, P<.001). Asterisks
indicate significant group differences, P<.05.
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When the order of drug and placebo administration was added as a fourth
independent group dimension, neither the main effect of order (F1,21 = 0.73, P = .40) nor the group x order
x region interactions (F3,63 = 0.39, P = .76) were statistically significant. In the posterior cingulate
(BA31 and BA29), the effect was reversed, with patients showing a greater
m-CPP response than controls (Figure 2).
An orthogonal set of individual planned comparisons confirmed that patients,
compared with controls, showed a significantly weaker m-CPP response in the
ACG (BA25) (F1,24 = 6.13, P = .02) but
a significantly greater m-CPP response in the posterior cingulate (BA29) (F1,24 = 7.92, P = .001). There were no significant
group effects for BA31 (F1,24 = 3.45, P
= .08) or for BA24 (F1,24 = .13, P = .71).
Statistical probability mapping (Figure 3) of drug minus placebo scores confirm the blunted response in the
ACG in patients (blue), especially slices z = 4 and z = -4, and the
greater response in the posterior cingulate (red, z = 12).
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Figure 3. Statistical probability map. Relative
metabolic rate differences (drug - placebo). Blue indicates that patient
response to meta-chlorophenylpiperazine (m-CPP) was less than that of normal
controls; red, patient response to m-CPP was greater than that of normal controls
(1- and 2-tailed t tests, P<.05).
Background is mean coregistered and shape-standardized magnetic resonance
imaging.
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Baseline.
Figure 4 shows mean rGMR in
the cingulate gyrus on the placebo scan day. To determine whether patients
and controls differed in baseline rGMR in the cingulate gyrus, we conducted
a 2 (group) x 4 (anteroposterior) x 2 (hemisphere) ANOVA on the
placebo scan data, which revealed a significant group x anteroposterior
region interaction (univariate F3,72 = 5.63, P = .008; multivariate Rao R3,22
= 7.12, P = .001). Compared with controls, patients
had lower rGMR in the posterior cingulate but not in the anterior (BA25) and
middle cingulate (BA24) regions. Individual planned comparisons confirmed
that patients had significantly lower rGMR than controls in BA31 and BA29
(F1,24 = 4.52, P = .04 and F1,24 = 9.88, P = .004, respectively). There were
no group differences for BA25 (F1,24 = 3.10, P = .09) and BA24 (F1, 24 = 1.24, P
= .27).
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Figure 4. Cingulate gyrus regions baseline
(placebo). Mean relative glucose metabolic rate (rGMR) in the cingulate gyrus
on the placebo scan day in normal controls and in patients with impulsive
aggression. Group x anteroposterior cingulate region interaction; F3,72 = 5.63, P = .008. Asterisks indicate significant group
differences, P<.05.
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rGMR AND CLINICAL RATINGS
Prefrontal Cortex
Baseline.
In controls during the placebo condition, increased rGMR was associated
with higher trait aggression scores (BDHItotal) in the right BA46
at the dorsal (rs = 0.61,
P = .027) and middle (rs = 0.69,
P = .009) slice levels. In addition, higher-measure subscale
BDHIIRR-ASS scores were associated with increased rGMR in BA46
bilaterally in the middle slice level (right:
rs = 0.581, P = .04; left:
rs = 0.61, P = .03 in the right
and left, respectively), and BA46 at the ventral slice level on the right
(rs = 0.64, P = .02), as well as in BA10
bilaterally at the middle slice level (right: rs = 0.49,
P = .08; left: rs = 0.56,
P = .05). In patients, increased rGMR was associated with higher scores
of aggression (BDHItotal) in the left BA46 at the middle- and ventral
slice levels (rs = 0.587,
P = .03; rs = 0.59,
P = .02, respectively). Similarly,
higher scores of aggression were associated with increased rGMR in the right
BA10 at the ventral slice level (rs = 0.639,
P = .02).
Effects of m-CPP.
In controls, decreased m-CPP response in BA47 bilaterally was associated
with higher BDHItotal score at the middle slice level
(rs = -0.61, P = .02;
rs = -0.62,
P = .02). In addition, lower BDHIIRR-ASSsubscales
were associated with increased rGMR in the left BA47 (rs = -0.55,
P = .05). An inverse correlation between rGMR and aggression
scores was also observed in BA45 bilaterally (rs = -0.61,
P = .03; and rs = -0.66,
P = .02). In patients, a direct correlation was seen between m-CPP
response in the right BA45 at the dorsal slice level (BDHItotal,
rs = .56, P = .04;
BDHIIRR-ASS, rs = 0.58,
P = .03) and in the right BA10 at the middle slice level
(rs = 0.57, P = .04).
Cingulate Gyrus
Baseline.
In the baseline (placebo) condition, increased rGMR in right and left
middle cingulate gyrus (BA24) in controls was associated with increased
BDHIIRR-ASS scores (rs = 0.59,
P = .03 and rs = 0.12,
P = .69, respectively). In contrast, increased rGMR in the left posterior
cingulate (BA29) was associated with increased BDHIIRR-ASS scores in patients
(rs = 0.52, P = .06).
Effects of m-CPP.
There were no significant Spearman correlations in either patients or controls between rGMR for
BA25, BA24, BA31, and BA29 and measures of aggression.
COMMENT
Patients with impulsive aggression react aggressively in response to
interpersonal emotional cues, such as conflict or perceived disrespect. We
hypothesized that limbic structures (ie, the hippocampus and amygdala) may
be activated by an interpersonal trigger. Then, through a mechanism facilitated
by serotonin, inhibitory regions (ie, the ACG and OFC) are activated. In our
current experiment, m-CPP provided a serotonergic activation that is expected
to activate inhibitory areas in normal subjects.
Our data show that in response to a serotonergic stimulus, rGMR in the
left medial posterior OFC is lower in patients with impulsive aggression compared
with controls. Alternative regions connected to the medial OFC, including
the lateral orbital cortex and areas of the frontal cortex, are activated
in patients. No group differences emerged in the baseline condition, suggesting
that differences between patients and controls can only be observed under
a serotonergic challenge. Although post hoc comparisons of the m-CPP response
between groups in individual frontal ROIs were not significant, the model
comparing drug activation between groups in medial vs lateral and orbital
vs dorsal areas was significant. This supports our a priori hypothesis, that
relative m-CPP rGMR in specific frontal areas (medial vs lateral; orbital
vs dorsal) would be diminished in patients with impulsive aggression.
In the cingulate cortex, there were important differences in responses
to m-CPP. The ACG (BA25) was activated in response to m-CPP in controls, whereas
in patients, it was deactivated. In contrast, the posterior cingulate was
deactivated in controls in response to m-CPP and was activated in patients
(Figure 2). The overall model entered
into the ANOVA and the post-hoc comparisons of responses to m-CPP in the ACG
and posterior cingulate were significant. This suggests that in patients with
impulsive aggression, activation of the posterior cingulate rather than the
ACG is the gateway to the inhibitory medial OFC. Activation of the posterior
cingulate is not accompanied by activation of the OFC and thus is less effective
in modulating aggression in patients than in normal subjects.
LATERALITY
The diminished m-CPP response in the ACG and the adjacent medial OFC
in patients was especially marked in the left hemisphere. Previous studies
of emotional processing and frontal lobe laterality have suggested that the
left hemisphere may be involved with "approach" and the right with "withdrawal,"50 Left frontal regions have been described as the center
for self-regulation and planning51 whereas
right frontal regions may be involved with negative affects, such as fear
and disgust.50 Traumatic brain injury in the
left dorsofrontal region gives rise to anger and hostility, whereas lesions
of the right OFC result in anxiety and depression.14
Phineas Gage's lesion was predominantly left-sided.16
The reported predominance of the left hemisphere in the control of emotion
was borne out in our study, which demonstrated a blunted metabolic response
to m-CPP in the left medial OFC in patients relative to controls. The opposite
effect was observed in the right OFC, where controls showed lower rGMR after
m-CPP than did patients. Findings of significant aggression-related laterality
have not been reported for the ACG and were not seen in our analysis.
MEASURES OF IMPULSIVE AGGRESSION AND rGMR
Clinical correlations between aggression and rGMR in the regions entered
into the ANOVAs were performed, although the groups were not comparable because
the scores of aggression fell into a much higher range in patients than in
controls. Controls demonstrated a direct correlation between the degree of
aggression and rGMR in BA46 bilaterally in the baseline condition. Patients
showed a similar effect but it was limited to the left hemisphere. In response
to m-CPP, however, controls with higher aggression scores exhibited increased
m-CPP activation in BA47 and BA45. In contrast, patients with higher aggression
scores showed lower m-CPP response in BA45 and no relationship in BA47. This
gives further evidence that patients and controls may use frontal brain regions
differently in regulating aggression.
In the cingulate region, there were no associations between m-CPP–stimulated
rGMR and the degree of aggression in controls or patients. Thus, the m-CPP
probe was sensitive enough to distinguish between groups that differ substantially
in impulsive aggression (ie, patients vs controls) but not to pick up differences
in the narrower range of aggressive behavior seen within groups.
The absence of patient-control differences in neuroendocrine responses
to m-CPP may be the result of relatively small numbers of subjects in each
cell, particularly when results are examined separately by sex. The use of
a serotonin stimulus in conjunction with 18fluorodeoxyglucose-PET
to examine specific activation of brain regions may be a more sensitive probe
for serotonergic dysfunction in impulsive aggression than the challenge paradigm.
This study used a serotonergic probe to activate ACG and OFC. Future
studies examining rGMR in response to aggression induction would provide even
more powerful evidence of the relationship between the activation of specific
brain regions and the control of aggression. Our study implicates the ACG
and the medial posterior orbital cortex in the control of aggressive behavior,
and suggests that serotonin may facilitate this control. m-CPP is known to
act as a partial agonist at 5-HT2A and 5-HT2C receptors,
but may also have a presynaptic site of action.52
As specific ligands become available, more specific pharmacologic targets
underlying the serotonergically mediated activation of the OFC and the ACG
observed with m-CPP can be identified.
AUTHOR INFORMATION
Submitted for publication December 12, 2000; final revision received
August 6, 2001; accepted October 1, 2001.
This research was supported by grant 5-RO1-MH566606 from the National
Institute of Mental Health, Bethesda, Md (Dr Siever), and by the Veterans
Affairs Medical Research Program Career Development Award, Washington, DC
(Dr New), and was supported in part by grant 5-M01 RR00071 from the National
Center for Research Resources, the National Institutes of Health, Bethesda
(for the Mount Sinai General Clinical Research Center).
This research was presented at the annual meeting of the Society of
Biological Psychiatry, New Orleans, La, May 5, 2001.
Invaluable editorial assistance was provided by Sherry Buchsbaum. Excellent
technical assistance was provided by Nina Roberto and Elizabeth Iskander.
Corresponding author: Antonia S. New, MD, Psychiatry Service-116A,
Bronx VA Medical Center, 130 W Kingsbridge Rd, Bronx, NY 10468 (e-mail: antonia.new{at}med.va.gov).
From the Psychiatry Service, Bronx Veterans Affairs Medical Center,
Bronx, NY (Drs New, Goodman, Reynolds, Koenigsberg, Silverman, and Siever,
Ms Mitropoulou, and Mr Sprung); the Department of Psychiatry (Drs New, Hazlett,
Buchsbaum, Goodman, Reynolds, Koenigsberg, Silverman, and Siever, Ms Mitropoulou,
and Messrs Sprung and Shaw), and the Neuroscience PET Laboratory (Drs Hazlett
and Buchsbaum, Mr Shaw, and Ms Platholi), Mount Sinai School of Medicine,
New York, NY.
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