Article

Positron Emission Tomography of Regional Brain Metabolic Responses to a Serotonergic Challenge in Major Depressive Disorder with and without Borderline Personality Disorder

Department of Psychiatry, Columbia University, College of Physicians & Surgeons, New York, NY, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 07/2005; 30(6):1163-72. DOI: 10.1038/sj.npp.1300689
Source: PubMed
ABSTRACT
Previous neuroimaging studies of major depression have not controlled for the presence of personality disorders characterized by impulsive aggressive behavior, such as borderline personality disorder (BPD). Using positron emission tomography (PET), we studied regional glucose uptake in response to fenfluramine (FEN) in depressed subjects with BPD (n=11) and depressed patients without Cluster B Axis II disorders (n=8). Subjects were scanned while medication-free after a single blind placebo administration and after FEN on a second day. Brain responses were measured by PET imaging of [18F]fluorodeoxyglucose (FDG) and serial prolactin levels. Scans were compared at a voxel level using statistical parametric mapping. Correlations of changes in relative regional cerebral uptake (rCMRglu) with clinical measures were assessed. Depressed borderline patients had greater relative activity in parietotemporal cortical regions (BA 40, BA 22, and BA 42) before and after FEN activation compared to those without BPD. They also had less relative uptake in the anterior cingulate cortex (BA 32) at baseline compared to depressed patients without BPD and FEN abolished this difference. Impulsivity was positively correlated with rCMRglu in superior and middle frontal cortex (BA 6 and 44). Hostility was positively correlated with rCMRglu in temporal cortical regions (BA 21 and 22). In conclusions, borderline pathology in the context of a Major Depressive Disorder is associated with altered activity in parietotemporal and anterior cingulate cortical regions. Controlling for the presence of BPD in future imaging studies of mood disorders may elucidate similarities and differences in regional serotonergic function in these two often comorbid disorders.

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Available from: Kevin M Malone, Jun 19, 2014
Positron Emission Tomography of Regional Brain Metabolic
Responses to a Serotonergic Challenge in Major Depressive
Disorder with and without Borderline Personality Disorder
Maria A Oquendo*
,1,2
, Aleksandra Krunic
1
, Ramin V Parsey
1,2
, Matthew Milak
1,2
, Kevin M Malone
2
,
Amy Anderson
2
, Ronald L van Heertum
1,2,3
and J John Mann
1,2,3
1
Department of Psychiatry, Columbia University, College of Physicians & Surgeons, New York, NY, USA;
2
Department of Neuroscience, New York
State Psychiatric Institute, New York, NY, USA;
3
Department of Radiology, Columbia University, College of Physicians & Surgeons, New York, NY, USA
Previous neuroimaging studies of major depression have not controlled for the presence of personality disorders characterized by
impulsive aggressive behavior, such as borderline personality disorder (BPD). Using positron emission tomography (PET), we studied
regional glucose uptake in response to fenfluramine (FEN) in depressed subjects with BPD (n ¼ 11) and depressed patients without
Cluster B Axis II disorders (n ¼ 8). Subjects were scanned while medication-free after a single blind placebo administration and after FEN
on a second day. Brain responses were measured by PET imaging of [
18
F]fluorodeoxyglucose (FDG) and serial prolactin levels. Scans
were compared at a voxel level using statistical parametric mapping. Correlations of changes in relative regional cerebral uptake
(rCMRglu) with clinical measures were assessed. Depressed borderline patients had greater relative activity in parietotemporal cortical
regions (BA 40, BA 22, and BA 42) before and after FEN activation compared to those without BPD. They also had less relative uptake in
the anterior cingulate cortex (BA 32) at baseline compared to depressed patients without BPD and FEN abolished this difference.
Impulsivity was positively correlated with rCMRglu in superior and middle frontal cortex (BA 6 and 44). Hostility was positively correlated
with rCMRglu in temporal cortical regions (BA 21 and 22). In conclusions, borderline pathology in the context of a Major Depressive
Disorder is associated with altered activity in parietotemporal and anterior cingulate cortical regions. Controlling for the presence of BPD
in future imaging studies of mood disorders may elucidate similarities and differences in regional serotonergic function in these two often
comorbid disorders.
Neuropsychopharmacology (2005) 30, 1163–1172, advance online publication, 16 March 2005; doi:10.1038/sj.npp.1300689
Keywords: depressive disorder; major; borderline personality disorder; positron emission tomography; fenfluramine; comorbidity;
serotonin
INTRODUCTION
A lifetime history of mood disorder is more common in
borderline personality disorder (BPD) than in other
personality disorders (Bunce and Coccaro, 1999). Indeed,
Zanarini et al (1998) noted an 83% lifetime prevalence of
Major Depressive Disorder (MDD) in BPD patients. Thus,
the two disorders often occur together. Apart from high
rates of comorbidity, BPD and MDD both appear to be
associated with low serotonergic activity (Coccaro et al,
1989; Oxenkrug, 1979; Siever et al, 1984). Although this
shared serotonin abnormality may be related to a history of
suicide attempt (Asberg, 1997) or impulsive aggression
(Brown et al, 1979), we have shown an additive deficiency in
the prolactin response to fenfluramine (FEN) due to the
presence of major depression, BPD, and a history of serious
suicide attempts (Malone et al, 1996). However, this
serotonergic deficiency may not just be additive; it may
also involve different neuroanatomical locations of seroto-
nin innervation.
Neuroimaging studies permit anatomical localization of
such abnormalities in vivo and can provide regional central
nervous system functional data when used in conjunction
with a serotonergic challenge. Serotonergic challenge with
an agent such as FEN has utility in the delineation of the
underlying psychopathology of affective disorders and
borderline personality disorders since it is likely that
Online publication: 10 January 2005 at http://www.acnp.org/citations/
NPP011005040370/default.pdf
Received 16 August 2004; revised 12 November 2004; accepted 7
January 2005
*Correspondence: Dr MA Oquendo, Department of Neuroscience,
New York State Psychiatric Institute, 1051 Riverside Drive Unit 42,
New York, NY 10032, USA, Tel: þ 212 543 5835, Fax: þ 212 543
6017, E-mail: moquendo@neuron.cpmc.columbia.edu
Neuropsychopharmacology (2005) 30, 11631172
&
2005 Nature Publishing Group All rights reserved 0893-133X/05
$
30.00
www.neuropsychopharmacology.org
Page 1
serotonergic dysfunction associated with these disorders
has both elements related to resting serotonergic tone as
well as responsivity to external stressors or provocations.
Moreover, it is likely that serotonergic dysfunction involves
different neurocircuits in these two frequently comorbid
conditions (see Mayberg et al (1999) and New et al (2002)
for review).
Although previous neuroimaging studies of BPD mostly
controlled for the presence of major depression (Juengling
et al, 2003; Soloff et al, 2000; Soloff et al, 2003), brain
imaging studies of major depression have not controlled for
the presence of BPD. Studies focusing on the identification
of serotonin abnormalities in MDD would benefit from
controlling for potential confounds, such as the presence of
other diagnoses associated with serotonergic dysfunction,
as is the case with BPD. Such an approach can more
accurately identify the neuroanatomical location of seroto-
nergic abnormalities specific to MDD.
This study used positron emission tomography (PET) of
regional cerebral uptake of [
18
F]fluorodeoxyglucose
(rCMRglu) in response to serotonin elevation after an acute
FEN challenge, relative to placebo challenge. With this
methodology, we examined regional brain serotonergic
function in major depression with comorbid BPD in
comparison to major depression without BPD. In addition
to comparing the two groups, we examined the effect of
measures of impulsivity, hostility, and aggression on central
serotonergic response as measured by rCMRglu after FEN.
We hypothesized that the presence of BPD in patients with
MDD would have a significant effect on cortical activity in
the orbitofrontal and anterior cingulate regions, areas that
play a central role in the regulation of aggressive and
impulsive behavior and that these regions would be
demonstrably associated with measures of these traits. To
our knowledge, this is the first study of glucose metabolism
in response to FEN in major depression that controls for
comorbid BPD.
METHODS
Subjects
A total of 19 female subjects diagnosed with a Major
Depressive Episode were included in this study. Informed
consent was obtained from all subjects after a complete
description of the study was provided. Eight did not have
BPD or other cluster B Axis II disorder, and 11 had
comorbid BPD. All but one patient with comorbid BPD were
right-handed. Analyses conducted excluding this subject
did not change results, so the data were preserved in the
sample. Axis I diagnosis was assessed through the
Structured Clinical Interview for DSM III R, Patient version
(SCID-P) (Spitzer et al, 1990) and Axis II diagnosis was
assessed with the SCID II-P interview (First et al, 1996). All
subjects had MRI examinations and had no radiological
evidence of neurological pathology. Exclusion criteria
included active medical illness based on history, physical
examination, and standard laboratory tests including liver
function tests, hematological profile, thyroid function test,
urinalysis, and toxicology; substance dependence in the last
6 months or substance abuse in the last 2 months; and
pregnancy.
Measures
Depression was rated using the 17-item Hamilton Depres-
sion Rating Scale (HAM-D) (Hamilton, 1960) and the Beck
Depression Inventory (BDI) (Beck et al, 1961). The Buss–
Durkee Hostility Inventory (BDHI) (Buss and Durkee, 1957)
and Brown Goodwin Lifetime Aggression Scale (BG) (Brown
et al, 1979) were used to rate hostility and aggression, and
the Barratt Impulsivity Scale (BIS) (Barratt, 1965) rated
impulsivity.
Medication Washout
All medications were discontinued for a minimum of 14
days prior to PET studies (6 weeks for fluoxetine and 1
month for oral antipsychotic). Only subjects failing an
adequate trial of medication were withdrawn from anti-
depressants. During the washout period, subjects were
allowed up to 3 mg of lorazepam daily. This was discon-
tinued 24 h before the scan. Premenopausal female subjects
were studied within 5 days after onset of menstruation and
were not on oral contraceptives.
FEN Challenge
Subjects had PET studies on two consecutive days after
fasting from midnight and throughout the challenge test as
previously described (Mann et al, 1996b; Oquendo et al,
2003). They received placebo on the first day and FEN on
the second day in a single blind design. This study was
conducted prior to the removal of FEN from the US market.
On each study day, an intravenous catheter was inserted at
approximately 0800 hours and a solution of 5% dextrose
and 0.45% saline was infused. Prolactin levels were drawn
15 min and immediately before FEN or placebo adminis-
tration to ascertain baseline levels. An oral dose of
approximately 0.8 mg/kg of dl-FEN (or identical pills
containing placebo) was administered at about 0900 hours.
Prolactin, FEN, and norfenfluramine levels were drawn
hourly for 5 h after medication administration. Subjects
remained awake during the procedure. Prolactin levels were
ascertained by immunoradiometric assay (McBride et al,
1989, 1990). The lower level of sensitivity of the method is
0.3 ng/m with an interassay coefficient of variation of 4%.
Prolactin response to FEN at each time point was calculated
as the difference between the prolactin level on FEN day
and the prolactin level at the corresponding time point
on placebo day. These values were compared between
depressed patients with and without borderline personality
disorder. FEN and norfenfluramine levels were measured by
a gas–liquid chromatography method (Krebs et al, 1984;
Myers et al, 1994).
PET Studies
Since FEN effects peak about 3 h after administration, and
in an attempt to capture the maximal response to FEN, a
bolus injection of approximately 5 mCi [
18
F]FDG was
administered 3 h after the administration of placebo or
FEN. Subjects gazed at a uniform visual stimulus (cross
hairs) in a dimmed room during the first 15 min of the
[
18
F]FDG distribution phase. After another 15 min, subjects
PET in MDD with and without BPD
MA Oquendo et al
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were transferred to the scanner where they lay supine.
A custom-made thermoplastic mask was used to minimize
head movement and obtain comparable head position
on the two scan days. The head was positioned so
that the lowest scanning plane was parallel to the
canthomeatal line and approximately 1.0 cm above it and
then the infrared light positions on the mask were marked.
For the second study, the head was positioned as closely as
possible to the first study by using the original mask with
the same marks. A Siemens ECAT EXACT 47 scanner (in
plane spatial resolution 5.8 mm, axial resolution 4.3 mm
FWHM at center) was used to acquire a 60 min emission
scan in 2D mode in a series of twelve 5-min frames.
The attenuation correction was measured by a 15-min
68Ge/68Ga transmission scan. Images were reconstructed
with a Shepp radial filter, cutoff frequency of 35 cycles
per projection rays and a ramp axial filter, cutoff frequency
of 0.5 s.
Image Analysis
Two types of comparisons were made. One type of
comparison was of differences in rCMRglu response to
FEN compared to response to placebo in the MDD group as
well as in the MDD with BPD group. The second type of
comparison was of differences in rCMRglu in the MDD
group compared with the MDD with BPD subjects after
placebo as well as a comparison of responses in the two
groups after FEN. These differences were evaluated using
Statistical Parametric Mapping (SPM 99), (SPM Web page,
2002, www.fil.ion.ucl.ac.uk/spm/software/spm99). Auto-
mated image coregistration (Woods et al, 1992) was used
to align the 12 frames within each study (Mann et al,
1996b). The resulting summarized image was transformed
into standard stereotaxic atlas space (Talairach and
Tournoux, 1988). Each image was smoothed by applying
an isotropic Gaussian kernel to increase the signal to noise
ratio. Analysis of covariance was applied within each
condition controlling for global CMRglu. For each group
(MDD only and MDD with BPD), the adjusted mean
rCMRglu and variance were computed at each voxel for
both placebo day and FEN day. These were used to compute
t-tests of the differences of the means between groups for
each study day at each voxel, and converted to Z-scores for
graphical display as parametric maps. All values were
corrected for multiple comparisons by SPM based on ‘the
theory of continuous random fields, assuming the statistic
image to be a good lattice representation of an underlying
continuous stationary random field. Results for the Euler
characteristic lead to corrected p-values for each voxel
hypothesis’ (SPM Web page, 2002, www.fil.ion.ucl.ac.uk/
spm/software/spm99).
Analysis of Effects of Clinical Parameters on rCMRglu
We calculated Pearsons’s correlations between proportion-
ally normalized rCMRglu values generated for the placebo
and FEN day and scores on the Barratt Impulsivity Scale,
Brown Goodwin Aggression Scale, and Buss–Durkee
Hostility Inventory.
RESULTS
Clinical Characteristics of Depressed Female Subjects
with and without BPD
Table 1 describes the clinical and demographic character-
istics of eight female patients with MDD and no Cluster B
Axis II diagnosis and 11 depressed female patients
with comorbid BPD. The two groups had comparable
severity of current depression, and lifetime impulsivity,
hostility, and aggression. Of 11 depressed patients with
BPD, seven (64%) had a history of at least one suicide
attempt. Of eight depressed patients without BPD, four
(50%) had a history of suicide attempt, a difference that was
not statistically significant (Table 1). Prolactin levels rose
significantly after FEN administration compared to after
placebo but there was no significant difference between
the two diagnostic groups in prolactin response to FEN
(p ¼ 0.62).
Effects of FEN Compared to Placebo on rCMRglu
Results below are of voxel-based analysis of rCMRglu
(analysis of covariance controlling for glucose metabolic
rate) after placebo (day 1) compared to after FEN (day 2)
administration in each group.
MDD With BPD. No areas of higher rCMRglu after
FEN relative to placebo were found in the group with
MDD with BPD. Subjects with MDD and BPD had an area in
the right medial temporal gyrus (BA 21) with lower
rCMRglu after FEN than after placebo (Figure 1). This
Table 1 Clinical and Demographic Characteristics of Depressed Patients with and without Borderline Personality Disorder (BPD)
Variable Major depressive disorder Major depressive disorder with BPD df TP(X
2
)
Age (years) 42.6715.7 32.078.9 17 1.87 0.08
HAM-D Rating Scale 17-item 21.573.6 22.476.3 17 0.35 0.73
Beck Depression Inventory 36.076.5 29.3713.7 15 1.19 0.25
Barratt Impulsivity Scale 48.0711.6 54.6717.4 12 0.83 0.42
Brown-Goodwin Aggression Scale 14.972.6 19.075.9 12.9 1.99 0.07
Buss–Durkee Hostility Inventory 28.477.7 37.2710.2 16 1.95 0.07
Suicide attempt (%) 50% (4/8) 64% (7/11) F Fisher’s Exact Test 0.45
PET in MDD with and without BPD
MA Oquendo et al
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finding did not reach statistical significance (corrected
p ¼ 0.067).
MDD without BPD. There was no difference in rCMRglu
after FEN compared to after placebo administration.
rCMRglu in MDD with BPD Compared to MDD without
BPD on Each of Two Study Days
Comparisons of rCMRglu after placebo were made between
the two groups. Similar comparisons were conducted after
FEN administration.
Regions where MDD with BPD subjects showed higher
rCMRglu than MDD without BPD subjects.
After placebo
administration (Figure 2a), there was a single major area of
higher rCMRglu on the right side in the group with MDD
with BPD (cluster size 2042, corrected p ¼ 0.007) encom-
passing the superior temporal (BA 22 and 42) and inferior
parietal gyrus (BA 40) when compared to the group with
MDD only. After FEN (day 2) administration (Figure 2b),
this area of greater rCMRglu (corrected p ¼ 0.013, cluster
size 1740) became modestly smaller.
Regions where MDD with BPD subjects showed lower
rCMRglu than MDD without BPD subjects.
After placebo,
a single area (Figure 2c) of lower rCMRglu (p ¼ 0.005) in the
left anterior cingulate (BA 32) was noted in the comorbid
MDD and BPD group when compared with the MDD only
group. This group difference was abolished after FEN
administration.
Relationship of PET Imaging Measures to Clinical
Parameters
Pearson’s correlations between clinical measures and
rCMRglu are reported for both the placebo and the FEN
administration days (Figure 3). After placebo administra-
tion, impulsivity correlated positively with rCMRglu in the
right superior frontal gyrus (BA 6) and BA 44 and this
association disappeared after FEN administration. At base-
line (after placebo), hostility correlated positively with
rCMRglu in the right middle temporal gyrus (BA 21) and
Figure 1 Subjects with major depressive disorder with BPD have an area
of decreased rCMRglu after FEN activation relative to placebo.
Extent of
Cluster P
(voxel)
Voxel height
corrected P
(Z)
Anatomic location Talairach
coordinates
(x,y,z)
0.067 (893) 0.292 (4.38) Right medial temporal
gyrus (BA 21)
53,1,24
Figure 2 (a) Subjects with MDD with BPD have an area of greater rCMRglu compared to subjects with MDD without BPD at baseline (after placebo
MMD þ BPD4MDD). (b) Subjects with MDD with BPD have an area of greater rCMRglu compared to subjects with MDD without BPD after FEN (MMD
þ BPD4MDD). (c) Subjects with MDD with BPD have an area of less rCMRglu compared to subjects with MDD without BPD at baseline (placebo day)
(MMD þ BPD4MDD).
Extent of Cluster P (voxel) Voxel height corrected P (Z) Anatomic location Talairach x,y,z
(A)
0.007 (2042) 0.031 (4.73) Right superior temporal gyrus (BA 22) 65,55,18
1.000 (3.03) Right superior temporal gyrus (BA 42) 63,26,16
1.000 (2.76) Right inferior parietal gyrus (BA 40) 55,50,45
(B)
0.013 (1740) 0.187 (4.23) Right medial temporal gyrus (BA 39) 63,59,16
0.594 (3.76) Right inferior parietal gyrus (BA 40) 65,37,35
1.000 (2.61) Right superior parietal gyrus (BA 40) 53,54,51
(C)
0.005 (2196) 0.989 (3.10) Left anterior cingulate (BA 32) 12,36,18
1.000 (2.81) Left postcentral gyrus (BA 6) 34,20,32
PET in MDD with and without BPD
MA Oquendo et al
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PET in MDD with and without BPD
MA Oquendo et al
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Figure 3 Correlations of relative regional cerebral glucose metabolism rate and clinical variables after placebo (day 1) or FEN (day 2) administration.
Clinical variables (no. of cases) Extent of cluster
P (voxel)
Voxel height
corrected P (Z)
Anatomic location Talairach X,Y,Z
Barratt Irnpulsivity Scale (14) BIS-day 1 0.000 (4261) 0.895 (3.51) Right superior frontal gyrus (BA 6) 8,10,49 r ¼ 0.81
0.035 (1317) 0.981 (3.26) (BA 44) 42,9,16 r ¼ 0.76
Buss–Durkee Hostility Inventory (18)
BUSS-day 1
0.028 (1504) 0.594 (3.75) Right medial temporal gyrus (BA 21) 46,5,19 r ¼ 0.77
Buss-Durkee Hostility Inventory (18)
BUSS-day 2
0.040 (1323) 0.908 (3.41) Left superior temporal gyrus (BA 22) 20,34,13 r ¼ 0.73
PET in MDD with and without BPD
MA Oquendo et al
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remained after FEN administration. Measures of aggression
did not correlate with rCMRglu in any regions on either
study day.
DISCUSSION
This study used a serotonergic probe to assess differences in
regional brain activity of depressed patients with and without
BPD comorbidity. We hypothesized that comorbidity of BPD
and MDD would have a significant effect on relative regional
brain activity in the anterior cingulate and orbitofrontal areas.
We found that depressed patients with comorbid borderline
pathology have lower activity in the anterior cingulate area at
baseline (placebo) when compared to patients with MDD
only. This difference was not present after serotonin
stimulation. In addition, depressed patients with borderline
pathology had greater relative activity in parietotemporal
regions at baseline and after serotonin stimulation, when
compared to depressed patients without borderline pathology.
Anterior Cingulate in MDD with BPD Compared to
MDD
We found lower regional activity in the anterior cingulate in
depressed patients with BPD compared to depressed
patients without BPD after placebo but not after FEN
stimulation. Lesion studies suggest that control of aggres-
sion may be mediated by the anterior cingulate gyrus and
orbitofrontal region (Butter et al, 1970; Grafman et al, 1996;
Heinrichs, 1989; Raleigh et al, 1979). Functional neuroima-
ging studies of brain glucose metabolism in borderline and
other aggressive and impulsive patients have also impli-
cated the anterior cingulate area. In agreement with our
findings, most studies of BPD found low relative glucose
metabolism and regional cerebral blood flow (rCBF) in the
anterior cingulate gyrus at rest (De La Fuente et al, 1997;
Goyer et al, 1994). PET studies report that FEN responses
are blunted in the orbitofrontal cortex and anterior
cingulate gyrus (Siever et al, 1999) in impulsive aggressive
subjects compared to healthy controls, as are m-CPP
responses (New et al, 2002), although not all studies agree
(Soloff et al, 2000). Moreover, a treatment study assessing
decreases in aggressive behavior after a 12 week course of
fluoxetine found that changes in cingulate and orbito-
frontal glucose metabolism were correlated to clinical
improvement, further supporting the importance of seroto-
nergic function in these regions and the regulation of
impulsive aggression (New et al, 2004).
We did not compare our subjects to normal controls, and
thus cannot compare our results to the abovementioned
studies directly. Our patients had BPD and comorbid with
Major Depression. The presence of active depression in our
subjects, which was not the case in samples studied by New
et al (2002) for example, may have impeded detection of
decreased responses to serotonergic challenge paradigms in
anterior cingulate and orbitofrontal cortex in our study
population because of the serotonergic hypofunction
associated with Major Depression. Nonetheless, our finding
supports the hypothesis that impulsive aggressive indivi-
duals such as those with BPD compared to nonimpulsive
individuals have lower relative glucose metabolism in the
anterior cingulate. This abnormality may be related to
disinhibition via ungated input from downstream limbic/
subcortical regions, such as the amygdala, that may
predispose to aggression (for a review, see New et al,
2002). Of note, in our study, lower rCMRglu in the group
with comorbid BPD was present during the placebo
challenge and not during the FEN challenge, consistent
with the notion that serotonin has serenic effects and may
have a role in reducing impulsive aggression as was noted in
a treatment study (New et al, 2004).
Orbitofrontal Cortex in MDD with BPD Compared to
MDD
We did not find a difference in the orbitofrontal cortical
area between depressed patients with BPD and MDD
without BPD in contrast to findings from both lesion
(Butter et al, 1970; Grafman et al, 1996; Heinrichs, 1989;
Raleigh et al, 1979) and neuroimaging studies (De La Fuente
et al, 1997; Goyer et al, 1994; New et al, 2002, 2004; Siever
et al, 1999) that suggest a role for the orbitofrontal cortex in
impulsive aggression. Our sample of depressed women with
BPD did not differ significantly in terms of clinical
measures of aggression and impulsivity from the depressed
women without BPD (see Table 1). It is possible that a
sample of more impulsive aggressive individuals in the BPD
group may have permitted detection of such an effect.
Alternatively, the effects of depression in this area may
overpower those of impulsivity in BPD as some functional
imaging studies have also suggested a role for the orbital
prefrontal cortex in the pathophysiology of depression. For
example, studies that examined abnormalities during a
Major Depressive Episode and after various forms of
treatment report normalization of orbitofrontal and ante-
rior cingulate abnormalities with treatment (Baxter Jr et al,
1989; Bench et al, 1995; Brody et al, 1999; Buchsbaum et al,
1997; Mayberg et al, 2000, 2002). Indeed, Bremner et al
(1997) found that depressed patients who were 6 weeks into
a course of antidepressant treatment exhibited decreases in
glucose metabolic rates in the orbitofrontal cortex and
thalamus after a tryptophan-depletion-induced acute re-
lapse compared to patients without depressive symptoms. A
comparable pattern of abnormality in the orbitofrontal
cortical region is seen in refractory depressed patients
(Mayberg et al, 1997) and in patients with depression
associated with neurological disorders (Bromfield et al,
1992; Mayberg et al, 1990, 1992). Mayberg et al (1999)
suggested that mood provocation in patients with acute and
remitted depression resulted in rCBF decrease in the medial
orbitofrontal cortex BA 10/11, which was absent in healthy
controls. She concluded that these regions might represent a
site of vulnerability in patients with unipolar depression.
Thus, the effects of the presence of Major Depression on
lowering rCMRglu in orbital frontal regions may obviate
our ability to detect effects of impulsive aggression.
Temporoparietal Cortical Region in MDD with BPD
Compared to MDD Alone
In our study, depressed borderline patients had greater
rCMRglu in parietotemporal cortical regions (BA 40, BA 22,
BA 42) before and after FEN activation compared to
PET in MDD with and without BPD
MA Oquendo et al
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depressed patients without BPD. One study using FDG
found no differences in temporal glucose metabolism in
subjects with BPD compared to healthy volunteers (De La
Fuente et al, 1994). Similarly, a study using a FEN challenge
design (Siever et al, 1999) has shown that impulsive
aggressive patients have no differences in temporal
rCMRglu compared to normal controls after placebo
administration. However, also using a FEN challenge
approach, Soloff et al (2000) found that borderline patients
showed greater rCMRglu in the left superior temporal gyrus
after placebo compared to normal controls, as was the case
in our study. In contrast, using PET and alpha-[11-C]
methyl-
L-tryptophan (aMT), Leyton et al (2001) demon-
strated lower aMT trapping in male and female patients
with BPD compared with healthy controls in the superior
temporal gyrus (BA 22) and the inferior parietal lobe BA 40
in men only, suggesting lower serotonin synthesis in those
areas. Thus, studies of resting or post placebo temporal
glucose metabolism in aggressive impulsive individuals
and in BPD are not all in agreement. Studies using
FEN challenge also show discrepant results after FEN
administration. BPD patients are reported to have decreased
response to FEN when compared to controls in left middle
and superior temporal gyrus (BA 21–22), left inferior
parietal lobe (BA 40), and left caudate body (Soloff et al,
2000). Similarly, impulsive aggressive patients have de-
creased regional metabolism in the right superior parietal
cortex following FEN challenge compared with healthy
volunteers (Siever et al, 1999). These two results are in
contrast to ours. Since our comparison group was
comprised of patients with MDD and impulsive aggression
measures were similar in the two groups, it is possible
that the observed increases in glucose metabolism in
temporoparietal regions on both the placebo and FEN
day are related to other characteristics of the BPD group.
BPD is a heterogeneous disorder and impulsive aggression
is only one of its features. Thus, this difference could
relate to affective dysregulation, dissociative symptoms,
rejection sensitivity, or other characteristics of the de-
pressed BPD sample. We do not have data to address this
possibility.
Of note, studies in MDD have implicated these regions as
well. PET studies of glucose metabolism in depressed
patients at rest have reported hypometabolism in parietal
cortex (Austin et al, 1992; Biver et al, 1994) and temporal
lobe (Post et al, 1987). Mayberg et al (1994) reported
hypometabolism in the inferior parietal region (BA 40)
along with the dorsal and ventral prefrontal cortex (BA 46),
and the anterior cingulate (BA 24) in depressed patients.
Mann et al (1996a) found blunted responses to FEN in
prefrontal and parietotemporal cortex and Meyer et al
(1998) in only parietotemporal regions. Taken together,
studies suggest that depressed patients have lower activity
in parietotemporal cortical areas, as is the case in most
studies of impulsive patients.
Psychopathology in BPD
The principal dimensions that have been the focus of
biological research in borderline pathology include im-
pulsive aggression and affective dysregulation (Koenigsberg
et al, 2001). Impulsive-aggression includes behaviors
directed toward the self or others, such as self-injury,
domestic violence, assault, suicide, and property destruc-
tion. In our study, hostility was associated with temporal
cortical activity (BA 21) and impulsivity with right PFC
areas (BA 6, BA 10) activity. Soloff et al (2003) reported
significant reduction in FDG uptake in BPD subjects relative
to healthy controls bilaterally in medial orbital frontal
cortex, including BA 9, 10, and 11 and suggested that it may
be associated with diminished regulation of impulsive
behavior in BPD.
We were unable to find a relationship between aggression
as measured by the Brown-Goodwin Aggression Scale and
rCMRglu in any region. Previous imaging studies have
implicated frontal and temporal brain region’s metabolic
changes to violence (Goyer et al, 1994; Volkow and
Tancredi, 1987). Raine et al (1997) reported reduced
glucose metabolism in PFC and posterior parietal cortex
of a severely violent and mostly male sample. Our lack of
findings may be due to the relatively low variance in
aggression scores among our subjects.
Suicide attempts are often viewed as a subtype of
aggressive behavior, and disturbance in the serotonergic
system characterized by reduced CSF 5-HIAA has been
associated with attempted or completed suicides in a variety
of populations (Oquendo and Mann, 2000). The presence
of suicidality in depressed patients has been suggested
to influence neuroimaging findings in prefrontal cortex
(Meyer et al, 1998). In our study given the similar
proportion of suicide attempts in both groups, it is unlikely
that the presence of a history of suicidal acts explains the
observed metabolic differences in the ACG. The findings
more likely reflect the association of these with aggressive
impulsivity or other features of BPD such as affective
instability. To our knowledge, there have been no neuro-
imaging studies of affective instability in personality
disorders. However, depressive states can have character-
istics that resemble those of BPD, such as the presence of
suicidal acts, intense episodic dysphoria, a profound sense
of emptiness, and increased affective lability. Just as there is
an overlap in clinical presentation between borderline and
depressed patients, neuroimaging studies also show sig-
nificant overlap of changes in characteristic cortical
regional activity patterns between MDD and BPD. Mayberg
et al (1999) has proposed that changes in mood and not the
overall diagnosis of MDD account for changes in activity
patterns, and perhaps the same is true in BPD. Future
imaging studies of depression should characterize impulsive
aggressive subjects without MDD in order to obtain a fuller
picture of brain activity pattern characteristic of major
depression or depressed mood itself.
Limitations
This study has some limitations. First, the results require
replication given the small sample size. Second, since the
study included only female subjects, findings cannot be
generalized to both sexes. However, regional CMRglu
differences between men and women have not been
consistently reported (Baxter Jr et al, 1989; Miura et al,
1990). Potential gender differences may exist in FEN
activation of CMRglu as there is evidence of gender effects
in serotonergic brain function, and rates of serotonin
PET in MDD with and without BPD
MA Oquendo et al
1170
Neuropsychopharmacology
Page 8
synthesis have been shown to differ by gender (Nishizawa
et al, 1997). Moreover, gonadal hormones are known to
affect serotonergic responsivity. We only studied women
within 5 days of the onset of menses who were not on oral
contraceptives. Nonetheless, hormonal variability may have
affected our results despite our attempts to limit any such
effects. Finally, this study did not make comparisons
between the two studied patient populations and normal
controls.
In conclusion, depressed borderline patients had lower
rCMRglu in the anterior cingulate gyrus and this activity
pattern appeared to be at least partially regulated by
serotonin. They also showed higher rCMRglu in parieto-
temporal cortical region compared to depressed patients
without BPD. These differences in the activity pattern
suggest that the presence of comorbid BPD may have an
impact on cortical activity and serotonin responsivity in
depressed subjects.
ACKNOWLEDGEMENTS
We thank Ms Batsheva Halberstam and Dr Dianne Currier
for their thoughtful input. Dr Yoram Yovell contributed to
the design and funding of the study. This study was
supported by NIMH MH40695, American Foundation for
Suicide Prevention, NARSAD.
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    • "This could either reflect a higher number of serotonin transporters with an increased capacity of presynaptic serotonin reuptake or an increased number of available binding sites, due to lower endogenous serotonin levels (Koch et al. 2007). Both the prefrontal cortex hypometabolism found in BPD as described above and impulsive aggression scores have been shown to improve after treatment with fluoxetine (New et al. 2004) or administration of the serotonin-releasing agent fenfluramine (Oquendo et al. 2005), in some – but not all (Siever et al. 1999; Soloff et al. 2000) – studies. Taken together, these data suggest a model in which impaired serotonergic facilitation of " top-down " control may underlie the hypothesized imbalance between prefrontal regulatory areas and limbic hyperresponsivity. "
    [Show abstract] [Hide abstract] ABSTRACT: While neurobiological studies have focused primarily on DSM-IV Axis I disorders, there is an emerging neurobiology of personality disorders. Specific neurocircuitry alterations have been identified as the biological underpinnings of the dimensional traits that underlie personality disorders. In this chapter, we review the most significant neuroimaging findings using PET and SPECT in relation to personality disorders and dimensions.
    No preview · Chapter · Jan 2014
  • Source
    • "Consistent with low serotonin transporter (SERT) binding in the PFC, Austin and colleagues (2002) observed localized deficits in SERT immunoreactivity in axons in the PFC of depressed suicides, suggesting less serotonergic innervation . More recently, regional brain metabolic responses to evoked serotonin release and other serotonin turnover studies measured in vivo using positron emission tomography have detected related PFC abnormalities in suicidal behaviour (Oquendo et al. 2005 ; Smith et al. 2009). Importantly, these findings are argued to be independent of other factors such as International Journal of Neuropsychopharmacology (2012), 15, 435–447. "
    [Show abstract] [Hide abstract] ABSTRACT: Although serotonin receptor and cytoarchitectonic alterations are reported in prefrontal cortex (PFC) in suicide and depression, no study has considered binding relative to neuron density. Therefore, we measured neuron density and serotonin transporter (SERT), 5-HT1A and 5-HT2A binding in matched suicides and controls. Suicides and normal controls (n=15 matched pairs) were psychiatrically characterized. Neuron density and binding were determined in dorsal [Brodmann area (BA) 9] and ventral (BA 47) PFC by stereology and quantitative autoradiography in near-adjacent sections. Binding index was defined as the ratio of receptor binding to neuron density. Suicides had lower neuron density in the gyrus of both areas. The binding index was lower for SERT in BA 47 but not in BA9; the 5-HT1A binding index was higher in BA 9 but not in BA 47, while the 5-HT2A binding index was not different between groups. SERT binding was lower in suicides in BA 47 but not BA 9, while 5-HT1A binding was higher in BA 9 but not BA 47. SERT binding negatively correlated with 5-HT1A binding in BA 47 in suicides. Neuron density decreased with age. The 5-HT1A binding index was higher in females than males. We found lower neuron density and lower SERT binding index in both PFC regions in suicides. More 5-HT1A binding with less SERT binding and the negative correlation in depressed suicides suggests post-synaptic receptor up-regulation, and it is independent of the difference in neuron density. Thus, abnormalities in both cortical neurons and in their serotonergic innervation are present in suicides and future studies will need to determine whether cortical changes reflect the trophic effect of altered serotonin innervation.
    Full-text · Article · May 2011 · The International Journal of Neuropsychopharmacology
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    • "Also, the site of the present IMPC deactivation is next to the site of deactivation imposed by fenfluramine in BA 32 in depressed subjects, in whom Kegeles et al. (2003) described a correlation between greater metabolic suppression and acute mood improvement during the challenge. In a study of depressed patients with and without borderline personality disorder, fenfluramine affected the metabolism in BA 11, 21, and 40 in a manner that depended on the presence of the personality disorder (Oquendo et al., 2005 ). Thus, in the IMPC, monoaminergic reactivity correlates with personality disorder and depression. "
    Dataset: File S1
    [Show abstract] [Hide abstract] ABSTRACT: Related paper by authors. This is a recently published paper to which the submitted ms refers (0.24 MB PDF)
    Full-text · Dataset · Dec 2009
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