Amygdala–Prefrontal Disconnection in Borderline Personality
Antonia S New*,1,2, Erin A Hazlett1,3, Monte S Buchsbaum1,3, Marianne Goodman1,2, Serge A Mitelman1,3,
Randall Newmark3, Roanna Trisdorfer1, M Mehmet Haznedar1,3, Harold W Koenigsberg1,2, Janine Flory1
and Larry J Siever1,2
1Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA;2Department of Psychiatry, Mount Sinai School of Medicine,
Bronx VA Medical Center, Bronx, NY, USA;3Department of Psychiatry and Neuroscience PET Laboratory, Mount Sinai School of Medicine,
New York, NY, USA
Abnormal fronto-amygdala circuitry has been implicated in impulsive aggression, a core symptom of borderline personality disorder
(BPD). We examined relative glucose metabolic rate (rGMR) at rest and after m-CPP (meta-chloropiperazine) with
18fluorodeoxyglucose (FDG) with positron emission tomography (PET) in 26 impulsive aggressive (IED)-BPD patients and 24 controls.
Brain edges/amygdala were visually traced on MRI scans co-registered to PET scans; rGMR was obtained for ventral and dorsal regions of
the amygdala and Brodmann areas within the prefrontal cortex (PFC). Correlation coefficients were calculated between rGMR for
dorsal/ventral amygdala regions and PFC. Additionally, amygdala volumes and rGMR were examined in BPD and controls. Correlations
PFC/amygdala Placebo: Controls showed significant positive correlations between right orbitofrontal (OFC) and ventral, but not dorsal,
amygdala. Patients showed only weak correlations between amygdala and the anterior PFC, with no distinction between dorsal and
ventral amygdala. Correlations PFC/amygdala: m-CPP response: Controls showed positive correlations between OFC and amygdala regions,
whereas patients showed positive correlations between dorsolateral PFC and amygdala. Group differences between interregional
correlational matrices were highly significant. Amygdala volume/metabolism: No group differences were found for amygdala volume, or
metabolism in the placebo condition or in response to meta-chloropiperazine (m-CPP). We demonstrated a tight coupling of metabolic
activity between right OFC and ventral amygdala in healthy subjects with dorsoventral differences in amygdala circuitry, not present in
IED-BPD. We demonstrated no significant differences in amygdala volumes or metabolism between BPD patients and controls.
Neuropsychopharmacology advance online publication, 3 January 2007; doi:10.1038/sj.npp.1301283
Keywords: amygdala; positron emission tomography; impulsive aggression
The Prefrontal–Amygdala Circuit
The concept that the prefrontal cortex (PFC) controls and
inhibits the amygdala and other limbic structures, termed
‘the reptilian brain’, was proposed many years ago (McLean,
1955). Abundant preclinical data indicate that areas of the
PFC exert inhibitory control over the amygdala. A series of
experiments in rats have shown that the medial PFC inhibits
activity in the basolateral amygdala by stimulating inhibi-
tory interneurons in the amygdala (Rosenkranz and Grace,
1999, 2002). Many other such studies that have shown this
phenomenon in rodents (al Maskati and Zbrozyna, 1989;
Halasz et al, 2002; Jinks and McGregor, 1997; McDonald
and Mascagni, 1996; Morgan and LeDoux, 1995; Zbrozyna
and Westwood, 1991). In primates, damage to the lateral
PFC causes a loss of inhibitory control in attention tasks
(Dias et al, 1996; Stefanacci and Amaral, 2002), whereas
damage to orbital frontal cortex (OFC) causes a loss of
inhibitory control in ‘affective’ processing and increased
aggression (Izquierdo et al, 2005). In the macaque monkey,
whereas both lateral and medial areas within OFC have
strong association with limbic regions, lateral OFC has
specific connections to the amygdala (Carmichael and Price,
In human beings, functional brain imaging provides an
approach in assessing the relationship between prefrontal
and amygdala function by examining the correlation
coefficients between activity in the two structures. Human
studies with18fluorodeoxyglucose (FDG)-positron emission
tomography (PET) and fMRI have suggested a significant
correlation between these two structures, but have primarily
been carried out in healthy subjects. The directionality of
Received 7 March 2006; revised 26 September 2006; accepted 2
*Correspondence: Dr AS New, Department of Psychiatry, Mount Sinai
School of Medicine, Box 1218, One Gustave Levy Place, New York,
NY 10029, USA, Tel: +1 212 241 0193, Fax: +1 212 824 2302,
Neuropsychopharmacology (2007), 1–12
& 2007 Nature Publishing GroupAll rights reserved 0893-133X/07 $30.00
these correlations has been inconsistent, with some studies
showing positive correlations between areas of PFC and
amygdala (Pezawas et al, 2005), and other studies showing
negative correlations (Hariri et al, 2000, 2003). Specifically,
one fMRI study during a perceptual task involving viewing
pictures of frightening faces showed significant negative
correlation between rostral anterior cingulate, but negative
correlations between amygdala and caudal anterior cingu-
late (Pezawas et al, 2005), whereas another study with a
similar task showed a negative correlation between right
PFC and amygdala activity (Hariri et al, 2000). Significant
negative correlations were also identified between the
response of the left amygdala and those of the right OFC
as well as the anterior cingulate (Hariri et al, 2003). An fMRI
study of surprised faces show increased activation of the
right ventral amygdala when the subject interpreted the face
negatively, whereas a positive interpretation of the face
yielded activation of OFC (Kim et al, 2003). A subsequent
study by the same group showed activation of lateral OFC in
response to negative vs positive sentences, whereas medial
OFC was activated in response to positive vs negative
sentences (Kim et al, 2004), suggesting that subregions of
OFC may play different roles in relation to amygdala
Studies of patients with affective disorder (Drevets et al,
1992) and post-traumatic stress disorder (Shin et al, 2005)
have tended to find negative correlations between specifi-
cally medial PFC and amygdala in patients but not controls,
suggesting coupling only in psychopathology. Recent data
suggest a role for serotonin in modulating connectivity
between PFC and the amygdala, with subjects carrying the
‘short’ allele of the serotonin transporter gene (a gene
possibly conferring a risk for mood disorders), showing
greater fMRI amygdala/medial OFC ‘coupling’ during an
emotional picture viewing task than those with only the
‘long’ allele (Hariri et al, 2006; Heinz et al, 2005; Pezawas
et al, 2005).
Subregions of the Amygdala in Emotion
Subregions of the human amygdala have been shown to
have specific functions, roughly organized on a dorso-
ventral dimension. The ventral amygdala includes primarily
the basolateral complex (BLC) and the dorsal nucleus of
the Central Nucleus (CN). Whalen et al (2001) suggest that
the human dorsal vs ventral designation within the amyg-
dala provides a means for incorporating numerous results
from the animal literature offering compelling evidence that
the BLC (located ventrally in the human) can be dissociated
behaviorally from the central nucleus (located dorsally in
the human) and is the component of the amygdala
predominantly involved in emotion modulation. Further,
they note that whereas expressions of fear appear to activate
the BLC and CN (ie ventral and dorsal amygdala), anger
may involve the CN to a lesser degree (than the BLC)
because less additional information concerning the stimulus
is required (Whalen et al, 2001). Furthermore, fMRI studies
by this group have shown that specifically the ventral
amygdala is in response to emotional stimuli (Kim et al,
2003, 2004). The ventral amygdala (basolateral amygdala in
rats)–OFC circuit role in associative encoding and aversive
odor was also supported in rat studies of amygdala activity
in OFC (Saddoris et al, 2005; Schoenbaum et al, 2003).
The amygdala has been implicated not only in the
processing of negative emotion in general, but also more
specifically in the production of aggressive behavior in
animal studies. Electric stimulation of the lateral nucleus of
the amygdala in cats results in predatory attack behavior
(Gregg and Siegel, 2001). In prairie voles, the medial
nucleus of the amygdala has been shown to be involved in
the regulation of aggression towards intruders (Wang et al,
1997). In primates, ablation of the amygdala bilaterally leads
to increased social affiliation and decreased aggression
(Emery et al, 2001; Meunier et al, 1999). These data have
been taken to demonstrate a central role for the amygdala
in the production of aggression, and led to the successful
use of unilateral amygdalectomy in the treatment of a small
number of cases of pathological aggression in human beings
(Sachdev et al, 1992).
Borderline Personality Disorder as a Prototype of
Borderline personality disorder (BPD) is an illness,
characterized by the symptom of emotional dysregulation
and disinhibited anger, which often leads to aggressive
behavior. The model of altered prefrontal–amygdala con-
nectivity provides a model for the primary symptom in
BPD, disinhibition of emotion. To date, however, ours is the
first study in BPD examining the relationship between
prefrontal regions and amygdala in BPD.
A number of studies have reported abnormal PFC in
BPD, as well as in impulsive aggressive subjects with a
variety of personality disorders. An18FDG-PET study repor-
ted reduced glucose metabolism in BPD patients compared
to healthy controls in PFC, and anterior cingulate bilaterally
(De La Fuente et al, 1997). In response to serotonergic
challenge, specifically impulsive-aggressive BPD patients
demonstrate decreased metabolism in anterior cingulate
and PFC, compared to controls (New et al, 2002; Siever et al,
1999b; Soloff et al, 2003). Numerous studies have demon-
strated decreased serotonergic responsiveness in impulsive
aggressive patients with personality disorders (Coccaro,
1989; Dougherty et al, 1999; New et al, 2004; O’Keane et al,
1992; Virkkunen et al, 1994), and impulsive aggression has
been shown to respond the treatment with SSRIs (Coccaro
and Kavoussi, 1997). We have recently reported gray matter
reduction in anterior cingulate (BA 24) in a large sample
of BPD patients (n¼50) compared with healthy controls
(n¼50) (Hazlett et al, 2005). In an analysis of a large
sample of BPD-(IED) impulsive aggressive subjects, we
found that male subjects with IED-BPD have hypometabo-
lism widely across the frontal lobe compared to healthy
men, healthy women and women with BPD in response to
placebo (New et al, under review). This finding extends our
prior finding of decreased rGMR in response to m-CPP in
IED-BPD in anterior and increase in posterior cingulate
compared to controls in a larger sample (New et al, 2002).
We find similar evidence of anterior cingulate decreases
and posterior cingulate increases in activation after seroto-
nergic stimulus. We report these findings in a separate
manuscript from the present one as they are conceptually
quite different. The present study is a correlational analysis,
AS New et al
examining the relationship of activity in different brain
regions, whereas our replications study closely follows
the analysis of our previous publication (New et al, 2002),
additionally exploring the role of aggression subtype and
sex on the findings.
To date, only few neuroimaging studies have evaluated
amygdala volume or activity in BPD and none specifically in
aggressive subjects. An early study of amygdala volume in
BPD showed that total amygdala volume tended to be
reduced in female BPD subjects compared to controls
(Driessen et al, 2000). Two subsequent studies also reported
decreased amygdala volume in BPD compared to controls in
relatively small samples (Schmahl et al, 2003; Tebartz van
Elst et al, 2003), although a recent study showed no differ-
ence in amygdala volume compared to controls (Brambilla
et al, 2004) and a VBM extension study showed decreases
only in the left hippocampus/amygdala complex (Rusch
et al, 2003; Tebartz van Elst et al, 2003). A recent larger
study employing a software package ‘BRAINS’ showed
no difference in amygdala volume in BPD compared to
controls, although those BPD patients with a concurrent
major depressive episode had larger amygdala volumes
compared to those without (Zetzsche et al, 2006).
Functional imaging studies of BPD are also limited in
number. One study of six female BPD patients and six
healthy volunteers (Herpertz et al, 2001) showed that BPD
patients had greater cerebral blood flow (BOLD) signal in
the amygdala bilaterally during unpleasant pictures com-
pared with neutral pictures than healthy controls. Another
study reported greater left amygdala activation in BPD
patients to facial expressions of emotion (vs a fixation
point) compared with healthy controls (Donegan et al,
Taken together, these studies provide support for a model
in which the amygdala is linked to emotional processing,
but it does not act in isolation; instead functions within a
network of brain regions that together modulate the
complex manifestations of emotion. This reciprocal inter-
action predicts that if cortical control of the thalamo-
amygdala pathway is reduced, emotional responses will be
dysregulated (LeDoux, 1994). Based on this literature, we
hypothesized that in BPD, an amygdala uncoupled from the
prefrontal regulation might be associated with loss of
behavioral control. In addition, the numerous data showing
abnormalities in serotonergic function in impulsive aggres-
sive patients with personality disorders led us to examine
the affect of a serotonergic agent on differential amygdala
connectivity with the prefrontal cortex. We further hypo-
thesized that these changes might be more marked for the
ventral than dorsal amygdala. Using18FDG-PET, we tested
the PFC-amygdala balance theory by comparing inter-
regional correlations between all 13 ipsilateral prefrontal
Brodmann areas and amygdala regions in impulsive
aggressive BPD patients compared with healthy controls
as measured at rest and after a serotonergic stimulus.
We predicted more robust correlations between medial
OFC (BA 11, 12, and 47) and specifically ipsilateral ventral
amygdala in healthy controls compared to patients. We
examined ipsilateral correlations as evidence suggests that
the reciprocal PFC–amygdala connections both in non-
human primates (Ghashghaei and Barbas, 2002) and in
human beings (Di Virgilio et al, 1999) are predominantly
ipsilateral. In addition, we examined group differences in
amygdala volume and metabolic activity at baseline and
after m-CPP. Data on regional metabolism in PFC and
cingulate on a subset of patients included in this study
(13 IED-BPD; 13 controls) have been published previously
(New et al, 2002).
MATERIALS AND METHODS
Twenty-six patients (17 men (35.7, SD¼7.9 years), nine
women (30.7, SD¼8.6), range¼20–48; 19 (right-handed),
four (left-handed), four (mixed)) meeting DSM-IV criteria
for BPD and Intermittent Explosive Disorder-modified
(IED) as defined by the Module for Intermittent Explosive
disorder (Coccaro et al, 1998) were included. Patients with a
history of schizophrenia, a psychotic disorder, or bipolar
(Type I) affective disorder were excluded. Patients with
current major depressive disorder were excluded. Patients
with past or current PTSD were accepted into the study, as a
relatively high rate of PTSD in community samples of BPD
has been reported (Swartz et al, 1990). Three (all male) of
the 26 BPD patients met criteria for current PTSD and one
female patient met criteria for past PTSD. We studied
borderline patients with impulsive aggression to find a
more homogeneous group of subjects with severe symp-
toms; this resulted, however, in our having a higher portion
of male subjects than is usually reported in BPD samples.
All subjects were medication-free 46 weeks (22/27 never-
medicated). Twenty-four age- and sex-matched healthy
subjects were also studied (15 men (31.7, SD¼7.9 years);
nine women (34.0, SD¼11.2) range¼21–58;19 (right-
handed), two (left-handed), three (mixed)). One RH 31-
year-old male control was inadequately imaged on the
m-CPP day owing to technical difficulties and was used only
in baseline analyses. Subjects were screened for severe
medical or neurological illness, head injury, or past sub-
stance dependence, as well as substance abuse in the prior
6 months. All subjects had a negative urine toxicology
screen, and females a negative pregnancy test on each scan
day. Participants provided written informed consent in
accordance with IRB guidelines. Patients were recruited
through advertisement in local newspapers (90%) and
referrals from psychiatric clinics at the Bronx VAMC and
Mount Sinai (10%). For the 26 subjects recruited into the
patient group, 164 subjects were screened. Patients were
excluded, in order of frequency for not fully meeting BPD,
current substance abuse, medical problems, pregnancy,
and/or current major depression. One subject declined
participation because of the radioactivity and another
declined an intravenous line. In the control group, 121
candidates responded to advertisement and 97 were exclu-
ded because of the presence of an Axis I or II diagnosis in
themselves or a first-degree relative.
Diagnoses were made through interviews by a psycho-
logist using the Structured Clinical Interview for DSM-IV
Axis I disorders (First et al, 1996) and the Structured
Interview for DSM-IV Personality Disorders (Pfohl et al,
1997), respectively followed by a consensus meeting.
Subjects and (when available with the patient’s consent) a
family member were interviewed. All patients met DSM-IV
AS New et al
criteria for BPD, except one subject who met 4/5 criteria
needed for a BPD diagnosis by his report and full criteria
by family-member report. Trait aggression was assessed
using the ‘Module for Intermittent Explosive Disorder-
Modified’ (Coccaro et al, 1998). All subjects completed the
Buss-Durkee Hostility Inventory (BDHI) (Buss and Durkee,
1957), the Barratt Impulsivity Scale (BIS-7b) (Barratt, 1965),
the Affective Lability Scale (ALS) (Harvey et al, 1989) and
the Childhood Trauma Questionnaire (CTQ) (Bernstein
and Fink, 1998).
All BPD patients had: significant physical and/or
verbal aggression, meeting criteria for IED (k¼0.92). All
patients met the ‘impulsiveness’ criterion for BPD (k¼0.78)
and 3/27 subjects met the ‘self-damaging’ BPD criterion
(k¼0.90). Controls met none of the above-defined criteria.
Handedness was determined with the Edinburgh-handed-
ness-scale (Oldfield, 1971). Table 1 shows group means
for symptom domains.
On two separate occasions (1–4 weeks apart), each partici-
pant received m-CPP or placebo in a double-blind counter-
balanced manner. After an overnight fast, an intravenous
line was inserted (for blood sampling and injection of
m-CPP/placebo/18FDG). 0.08-mg/kg of m-CPP/placebo was
given by slow push, immediately followed by 5mCi of
18FDG. The subject remained resting in a sound-attenuated,
dimly-lit room for the 35-min tracer-uptake period.
Following uptake, subjects were positioned in the PET
scanner for a 45-min data-acquisition period. This method
has been described in detail in previous reports (New et al,
PET scans were carried out as described elsewhere
(Haznedar et al, 1997; New et al, 2002) (GE2048 head-
dedicated scanner, resolution 4.5mm in plane, 5.0mm
axially). Fifteen slices at 6.5-mm intervals were obtained in
two sets to cover the entire brain. Slice counts of 1.5–3M
counts are typical. Scans were reconstructed with a blank
and a transmission scan using the Hanning filter. The same
individually molded thermoplastic facemask was used for
each scan to minimize head-movement during image
acquisition and to assist in PET/MRI coregistration. PET
images were obtained in nanocuries/pixel and standardized
as rGMR by dividing each pixel by the mean value for the
entire brain (defined by brain-edge from coregistered MRI).
Although this limits interpretations of single structure
absolute activity, this method is widely used when evaluat-
ing hypotheses related to patterns of metabolic rate across
brain areas and was used in earlier imaging studies of
serotonin activation (Mann et al, 1996; New et al, 2002;
Siever et al, 1999a; Soloff et al, 2000). PET–MRI coregistra-
tion used the algorithm of Woods et al (1993). Brain edges
were visually traced on all MRI axial slices with inter-tracer
reliability of 0.99 on 10 subjects.
Regions of Interest Approach
We assessed rGMR within BAs by tracing coronal slices
based on a digitized brain atlas with 33 coronal slice
maps of BAs defined by microscopic examination of an
entire postmortem brain, a technique detailed elsewhere
(Buchsbaum et al, 2001, 2002; Hazlett et al, 2000; Mitelman
et al, 2005). To assess the effect of m-CPP on rGMR,
the dependent measure for PET analyses on drug effect
was expressed as difference scores (m-CPP-placebo) for
rGMR within each BA, calculated by subtracting placebo
counts for each region of interest in each subject from the
corresponding rGMR from the m-CPP scan.
The amygdala was outlined on coronal MRI sections
using previously published methods (Haznedar et al, 2000)
(ICC¼0.82, area measured on three slices at the 25th, 50th,
and 75th percentiles of anteroposterior distance). Outlining
of the amygdala began at its largest extent (approximately
the center in the anteroposterior dimension) where clear
boundaries between gray matter and surrounding white
matter are visible. At this mid-section, the amygdaloid
complex is roughly elliptical in shape, and anatomical
margins are defined by the cornu ammonis and the white
matter of gyrus ambiens in the medial aspect, the cornu
inferius of the lateral ventricle in the ventral aspect, the
temporal lobe white matter laterally, and the gyrus semi-
lunaris in the dorsal aspect. Using an edge contrast-
enhancing technique (gradient filter) (Haznedar et al,
2000), we were able to visualize better the dentate gyrus
of the hippocampus and boundaries between the hippo-
campus and the amygdala. The posterior portions of the
amygdaloid complex were outlined by using the ventricular
recess, hippocampus, and gyrus semilunaris as reference
points (Figure 1). Anteriorly, the amygdaloid complex
gray matter is more heterogeneous and hard to identify.
We outlined from the midsection forward using gradient
filtering and excluded the entorhinal cortex, which may
include the inferior amygdala. The outlining ended at the
first coronal MRI section on which there was visible white
matter between the amygdala, ambiens, and white matter
of the entorhinal cortex. This procedure may have omitted
the very anterior end of the amygdaloid complex, but it
had the advantage of excluding other extraneous structures
from our analysis. Following the suggestion of Kim et al
(2003) we divided the amygdala into a top and bottom half,
based on the vertical distance on the mid-coronal slice and
Table 1 Clinical Assessments in IED-BPD and Controls
BDHI* ALS*BIS-7B* CTQ*
These are clinical measures for patients and controls. For aggression (BDHI) scores, affective instability (ALS), impulsivity (BIS) and childhood trauma exposure (CTQ)
all significant at po0.001. 2-tailed corrected for multiple comparisons.
*Groups are significantly different at a level of po0.001.
AS New et al
applied the MRI-traced template to resliced and coregis-
tered coronal PET slices. Volume is expressed as absolute
volume in mm3and relative to whole brain volume. The
data were assessed for movement artifact by measuring
the ratio of the area of the middle PET slice (obtained
by a radial edging algorithm which draws the edge at 62%
of the maximum value) to the area of the middle MRI
slice (obtained by hand-tracing); head-movement during
the longer scan would tend to blur the image and enlarge
the area of activity. No group difference for movement
artifact was detected (normals¼0.96770.031, patients¼
Pearson’s correlation coefficients were employed for frontal
BAs and regions of the amygdala with significance level of
po0.05. The Kullback’s w2test for correlational matrices
was employed to test group differences in correlational
matrices (Kullback, 1967). The Kullback test provides one
single p-value for comparing two correlation matrices each
from a separate group of subjects. This avoids the Type I
error associated with multiple correlation testing because
only one comparison is made. Univariate tests can then be
supplied as post hoc tests to locate major sources of matrix
differences. Mixed-factorial repeated-measures ANOVAs
were employed to examine group differences in amygdala
volume and metabolism. In addition, Pearson’s correlation
coefficients were used to test correlation between amygdala
activity and the ALS, BIS, BDHI and CTQ scores. All
correlations are reported for po0.05, two-tailed.
ANOVAs examining amygdala volume and function
were conducted both including and excluding the subjects
meeting PTSD, as PTSD has been associated with both
increased (Protopopescu et al, 2005; Shin et al, 2004), and
decreased amygdala activity (Britton et al, 2005); amygdala
volume in PTSD has been shown not to be different from
controls (Bremner, 2002; Wignall et al, 2004).
Correlations PFC and Amygdala
Placebo condition: correlations PFC and amygdala. The
correlations between the ventral amygdala and orbitofrontal
BA 11, BA 12, and BA 47 were positive and significant in
controls on the right; whereas on the left, they were positive
but not significant in BA 11, BA 12, and BA 47 (Table 2a).
In contrast, the IED-BPD group showed no significant
correlations between right or left ventral amygdala and OFC
(BA 11, 12, 47) (Table 2a). In addition to OFC, controls
showed positive correlations between subgenual BA 25
and ventral amygdala on the right and between BA 44 and
ventral amygdala bilaterally. Controls showed no significant
positive correlations between any frontal BAs and dorsal
amygdala in either hemisphere. Patients showed no signi-
ficant positive correlations between frontal BAs and either
dorsal or ventral amygdala at rest. In patients, there were
significant negative correlations between the dorsal and
ventral amygdala and BAs 6, 8, 9, 10, 32, and 46 bilaterally.
To test for group differences in the correlation matrices
for ventral/dorsal amygdala with frontal BAs for each hemi-
sphere, a Kullback’s w2test was conducted (Kullback, 1967).
Controls differed significantly from patients in correlations
between prefrontal BAs and dorsal and ventral amygdala in
both hemispheres (right ventral amygdala: df¼91, Kull-
back’s w2¼236.853, po0.0001; right dorsal amygdala:
df¼91, Kullback’s w2¼193.939, po0.001; left ventral
amygdala, df¼91, Kullback’s w2¼194.290, po0.001; left
dorsal amygdala, df¼91, Kullback’s w2¼184.355, po0.001)
(see Figure 2). The most striking group differences occurred
in correlations between right ventral amygdala and orbital
BAs 11, 12, and 47. Figure 3 shows scatter plots of rGMR for
correlations between these orbital BAs in the right hemi-
sphere and ventral amygdala.
m-CPP-placebo condition: correlations PFC and amyg-
dala. In response to m-CPP, controls showed significant
positive correlations between ventral amygdala and BA 12
and 25 on the left. In addition, controls showed significant
positive correlations for m-CPP-placebo rGMR between
dorsal amygdala and left BA 11 and 12 and right BA 11 and
25. In controls, the frontal pole correlated negatively with
dorsal amygdala in response to m-CPP in right BA 6 and 8
(see Table 2b). Patients, in contrast had positive correla-
tions between dorsal amygdala and dorsolateral PFC BA
44,45 and 46 on the left and between ventral amygdala and
dorsolateral PFC in BA 44 and 45. In addition, patients
showed a positive correlation between BA 12 and left ventral
amygdala and a negative correlation between dorsal
amygdala and BA 8 on the left.
Also for m-CPP-placebo, controls differed significantly
from patients in correlations between the prefrontal BAs
and ipsilateral dorsal and ventral amygdala in both hemi-
w2¼190.04, po0.001; right dorsal amygdala: df¼91, Kull-
back’s w2¼248.71, po0.001; left ventral amygdala, df¼91,
(c) Amygdala outlined.
Tracing the amygdala. (a) Coronal MRI: anterior–posterior dimension of amygdala. (b) Sobel-gradient filter to enhance gray/white boundaries.
AS New et al
Kullback’s w2¼169.10, po0.001; left dorsal amygdala,
df¼91, Kullback’s w2¼194.40, po0.001) (see Figure 4).
Group Differences in Amygdala Volume and
Although our hypothesis in this study was that the coupling
of metabolic activity between frontal BAs and ventral
amygdala would be disrupted, we also tested simple group
differences in amygdala volume and metabolism.
Amygdala volume. Because of evidence for specificity of
ventral amygdala in human emotion, we divided the
amygdala into dorsal and ventral components. A group
(control, patient)?hemisphere (R, L)?region (dorsal,
ventral) repeated-measures ANOVA with dorsal and ventral
Table 2 Correlations Frontal Brodmann Areas and Amygdala: Placebo and m-CPP-Placebo Condition
BA6BA8 BA9BA10 BA11 BA12BA24 BA25BA32 BA44 BA45BA46BA47
Right dorsal amygdala ?0.43*
Left dorsal amygdala
Right ventral amygdala ?0.46*
Left ventral amygdala
Right dorsal amygdala ?0.50*
Left dorsal amygdala
Right ventral amygdala ?0.61*
Left ventral amygdala
Right dorsal amygdala ?0.57*E?0.55*E?0.33
Left dorsal amygdala
Right ventral amygdala ?0.29
Left ventral amygdala
Right dorsal amygdala0.05E
0.15Left dorsal amygdala
Right ventral amygdala ?0.21
Left ventral amygdala
Relative glucose metabolism (rGMR) correlations between frontal lobe brodmann areas and dorsoventral amygdala divisions for placebo (a) and m-CPP-placebo (b).
Asterisks denote significant Pearson correlation coefficients (po0.05). Diamonds denote significantly different correlations for patient group from control group for a
particular region of interest, (po0.05, two-sided).
Red demonstrates significant positive correlation coefficients between indicated brain regions, whereas bold indicates significantly negative correlation coefficients
between brain regions.
correlations between rGMR in frontal Brodmann areas on the orbital surface of the brain and rGMR in ipsilateral amygdala in healthy subjects on the left and
in impulsive aggressive borderline personality disorder subjects on the right. Significant positive correlations at po0.05 are shown in red and significant
negative correlations in blue.
Correlations orbital floor and amygdala: placebo condition, This is a visual map of significant positive and negative as well as non-significant
AS New et al
amygdala volume as the dependent variable showed no
main effect of group or interaction with group. The same
result was found with relative amygdala volume (amygdala
volume/whole brain volume). It should be noted that the
total amygdala volumes found in our healthy subjects fall
well within the range of that found by others. Specifically,
we found total amygdala volumes for healthy control
subjects (mathematically identical of the sum of the top
and bottom for each hemisphere) to be: right hemisphere:
13657198mm3for women, 13977208mm3for men; left
hemisphere: 11987254mm3for women, 13657225mm3
for men. This is within the range for normal human
amygdala volumes found by others ranging from 1050 to
1600mm3for the right amygdala and 1140 to 1400mm3for
the left amygdala (Convit et al, 1999; Driessen et al, 2000;
Szabo et al, 2003).
Similarly, when the same analysis was conducted exclud-
ing subjects meeting criteria for PTSD, no significant effect
12, 47 and ventral amygdala illustrating distribution in controls and in IED-BPD.
Scatterplots right hemisphere OFC/ventral amygdala. Scatterplots of correlations of orbital Brodmann areas and amygdala rGMR for right BA 11,
significant correlations between rGMR for m-CPP minus placebo in frontal Brodmann areas on the orbital surface of the brain and rGMR for m-CPP minus
placebo in ipsilateral amygdala in healthy subjects on the left and in impulsive aggressive borderline personality disorder subjects on the right. Significant
positive correlations at po0.05 are shown in red and significant negative correlations in blue.
Correlations orbital floor and amygdala: m-CPP- Placebo Condition. This is a visual map of significant positive and negative as well as non-
AS New et al
of group in relative volume was detected. The groups
did not differ in whole brain volume (controls mean 1190,
p¼NS) (see Table 3).
patient)?hemisphere (R, L)?region (dorsal, ventral)
repeated-measures ANOVA with placebo rGMR in the
dorsal/ventral amygdala as the dependent variable showed
no main effect of group or significant interaction with
group. Similarly, there was no interaction involving group
for rGMR in the whole amygdala. The same result was
found when excluding the subjects with PTSD.
Amygdala metabolism (m-CPP-placebo). A group (con-
trol, patient)?hemisphere (R, L)?region (dorsal,ventral)
repeated-measures ANOVA with rGMR m-CPP?placebo
difference scores within regions of the amygdala as the
dependent variable showed no interaction involving group.
The same result was found when excluding the subjects
Correlations of volume/metabolism with clinical symp-
toms. To examine the relationship between metabolism and
symptom dimensions, we examined correlations between
volume and metabolism and clinical measures of impulsiv-
ity, aggression, and affective instability.
Amygdala volume. We observed a negative correlation
between BIS score and right relative ventral amygdala
volume in controls (n¼22, r¼?0.45, po0.001), but not
patients (n¼23, r¼?0.27, p¼NS) (between-group test of
correlation differences was not significant). In patients, we
found a negative correlation between impulsivity scores and
left ventral amygdala volume (n¼23, r¼?0.42, po0.004),
not present in controls (n¼22 r¼?0.08, p¼NS) (between-
group test of correlation differences was not significant).
These correlations survive Bonferroni correction for multi-
ple comparisons for which a p-value o0.004, two-tailed,
Amygdala activity. In patients, but not controls, we obser-
ved a negative correlation between aggression and affective
lability scores for placebo rGMR in right ventral and dorsal
amygdala (BDHI: ventral, r¼?0.67, dorsal r¼0.63; ALS:
ventral, r¼?0.67, dorsal r¼?0.68). For drug-placebo, in
controls but not patients, we observed negative correlations
between ALS scores and the ventral amygdala (controls
r¼?0.64) (Bonferroni corrected significance, po0.002,
two-tailed) (between group test of correlation differences
was not significant).
Implications of Group Differences in Fronto-Amygdala
The most striking finding that we report is the highly
significant normal-BPD group differences in correlation
patterns between frontal BA and ipsilateral amygdala meta-
bolic activity (m-CPP minus placebo as well as the resting
condition). Healthy controls, both at rest and in response
to a serotonergic probe, show positive correlations bet-
ween OFC (BA 11, 12) and right ventral amygdala, as was
predicted from the model of the ventral amygdala as the
component of human amygdala most closely associated
with frontal lobe emotion modulation (Kim et al, 2003;
Somerville et al, 2004; Whalen et al, 1998). This correla-
tional approach is based on the assumption that significant
correlations may reveal an important functional relation-
ship between the structures as discussed by Katz et al
(1996). Correlations in healthy controls support the idea of
intact coupling between PFC, particularly the ventrolateral
region (BA 11, 47 and more dorsally in BA 44), and right
ventral amygdala, a tight coupling which may be the neural
substrate for downregulation of the amygdala in response to
aversive stimuli. The absence of such tight coupling in BPD
patients, indicated by the lack of significant correlations
between OFC and amygdala, suggests a disconnect between
OFC and amygdala, which may explain the failure of BPD
patients to downregulate the amygdala in response to
aversive stimuli. Furthermore, the BPD patients appear to
have lost anatomic specificity of ventral vs dorsal amygdala,
showing nonsignificant correlations with OFC and modest
negative correlations between amygdala and widespread
regions of the frontal lobe.
The directionality of correlations between amygdala and
PFC is inconsistent in the literature. Our studies are
consistent with findings of Pezawas et al, in which rostral
areas of anterior cingulate showed positive correlations with
amygdala, at least under certain conditions (Kim et al, 2004;
Pezawas et al, 2005). However, other studies have demon-
strated negative correlations between amygdala and medial
OFC (Hariri et al, 2000, 2003). Previous fMRI studies
showing negative correlations between amygdala and OFC
have employed event-related designs showing acute reac-
tions to aversive stimuli (Dougherty et al, 2004; Shin et al,
2005). Our study, in contrast, employs18FDG-PET, which
reflects an average of activity of a 30-min epoch. As FDG
uptake appears to reflect metabolic activity at axon
terminals (Sokoloff, 1982), positive correlations would arise
between areas that receive input causing firing and its area
of efferent connection (Katz et al, 1996). A limitation of the
Table 3 Amygdala Volume
Right dorsal amygdala 919 (155)889 (141)
Left dorsal amygdala888 (158)861 (153)
Right ventral amygdala 1004 (140)926 (149)
Left ventral amygdala956 (162)927 (194)
Relative to whole brain?1000, mean, SD
Right dorsal amygdala 0.11 (0.02)0.10 (0.02)
Left dorsal amygdala 0.10 (0.01)0.10 (0.02)
Right ventral amygdala0.12 (0.02) 0.11 (0.02)
Left ventral amygdala0.11 (0.01) 0.11 (0.02)
Absolute volume in mm3and relative to whole brain volume for dorsoventral
AS New et al
correlational approach using FDG is that it does not discri-
minate between inhibitory and excitatory connections.
Another reason for inconsistencies in the literature
arise from the specific brain regions examined. Findings
of a negative correlation between the regions of PFC and
amygdala have been found with the rostral anterior
cingulate (Pezawas et al, 2005), as well as in ventral regions
of PFC (Hariri et al, 2000, 2003). Our finding of positive
correlations between particularly lateral OFC and ventral
amygdala in healthy subjects (not found in our borderline
group) is consistent with regional specificity of the
connection between amygdala and PFC shown in primate
studies (Carmichael and Price, 1995), and some human
studies however (Kim et al, 2004).
The ventral amygdala has been suggested to have greater
interconnection with OFC whereas the dorsal amygdala has
greater interconnection with the cingulate and other limbic
areas (Aggleton and Saunders, 2000). In our data, cingulate
areas left 24 and right 25 were both significantly correlated
with ventral but not dorsal amygdala, consistent with the
general pattern of greater ventral amygdala–cortical links,
but not with a distinction between cingulate and OFC
connections with the amygdala.
We show no significant group differences in rGMR bet-
ween BPD patients and controls in the amygdala, which may
suggest that the primary abnormality in BPD relates to the
failure of the PFC to ‘come on line’ in response to amygdala
activation. Group differences in correlations in response
to serotonergic stimulation show healthy controls with
positive correlations between orbitofrontal areas (BA 11,
bilaterally; left BA 12) and dorsal amygdala (Table 2b). This
is consistent with evidence that the dorsal amygdala (central
nucleus) is rich in neuronal fibers positive for serotonin
and serotonin-transporter in primates (Freedman and Shi,
2001). Borderline patients show positive correlations bet-
ween dorsal and ventral amygdala and dorsolateral BAs.
Implications of Lack of Group Differences in Amygdala
Volume and Activity
Consistent with larger studies in the literature employing
‘BRAINS’ to delineate the amygdala, our hand-tracing of
amygdala in a large sample show no difference in amygdala
volume between BPD and controls. Although some studies
have shown group differences, these studies have employed
exclusively female subjects, where as we include both men
and women and have selected BPD subjects with impulsive
aggression. We explored our data to examine whether
entering sex into the ANOVA would yield significant results
and found no main effect of sex or interaction between
sex and diagnosis in amygdala volume.
Clinical correlation with volume show some laterality in
that inverse correlations were seen in patients between right
ventral amygdala and measures of impulsivity, but in left
ventral amygdala in controls. Prior studies of amygdala
volume decreases in BPD, however, have shown a bilateral
effect. Clinical correlations in amygdala activity revealed
inverse correlations with affective instability and aggression
with right ventral and dorsal amygdala in BPD, whereas in
controls, a negative correlation between right ventral
amygdala and affective lability was observed. This supports
our evidence that there is a loss of anatomic specificity
between the ventral and dorsal amygdala in BPD. There was
no relationship between aggression scores and left ventral
amygdala volume in controls in part because the variance in
aggression measures within the controls group was very
This study has a number of limitations in design and
analysis. The lack of group differences in activation in
amygdala may relate to the study design, which did not
employ a behavioral task. As there was a pharmacological
challenge, the interaction with an impulse control task
would have required four scans instead of two, and this
would have provided logistical and subject volunteerism
problems. The responsivity of the amygdala may not be
adequately probed with a resting scan or with a pharmaco-
logic challenge. Future studies involving behavioral provo-
cation during functional scanning will elucidate this. In
addition, our statistical analysis employed a broad assess-
ment of correlations between all prefrontal Brodmann
areas in each hemisphere as well as the ventral and dorsal
amygdala. However, as functional imaging studies, present
and future, are producing a large number of activation areas
from exploratory mapping, the full presentation of the
correlation matrix seemed justified to provide findings
for other exploratory imaging studies.
Another limitation of the present study is the lack of
precision of our top-bottom parcellation of the amygdala.
The amygdala ROI has a volume of about 1300mm3in
our tracings. The full-width half-maximum resolution of
our scanner measured at the center of the ring is 4.5mm
in plane and 6.5mm in the z-axis. This yields a volume of
131mm3and the amygdala volume is thus approximately
10 times as great. The mean height of our amygdala tracing
on the coronal ROI is 14.3mm, and encompasses two PET
slices. Nevertheless, top and bottom amygdala values are
one-half as high, and partial volume effects limit our statis-
tical power to detect differences. In addition, our division
into top and bottom half is geometrical and does not weight
the lateral basal portion. MRI images provide inadequate
resolution to easily trace individual amygdala nuclei, again
reducing statistical power.
This research was supported by NIMH Grants MH566606
to Dr Siever, MH067918 to Dr New, and MH60023 to
Dr Buchsbaum, and by the VA Medical Research Program
(Career Development Award) to Dr New and a NARSAD
Independent Investigator Award to Dr Hazlett. This work
was also supported in part by a grant (5-M01 RR00071) for
the Mount Sinai General Clinical Research Center from the
National Center for Research Resources, at the NIH.
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