DEPRESSION AND ANXIETY 23:133–138 (2006)

Research Article
REGIONAL CEREBRAL BRAIN METABOLISM CORRELATES
OF NEUROTICISM AND EXTRAVERSION
Thilo Deckersbach, Ph.D.,1 Karen K. Miller, M.D.,2 Anne Klibanski, M.D.,2 Alan Fischman, M.D., Ph.D.,3
Darin D. Dougherty, M.D.,1 Mark A. Blais, Psy.D.,1 David B. Herzog, M.D.,1 and Scott L. Rauch, M.D.1

Factor-analytic approaches to human personality have consistently identified

several core personality traits, such as Extraversion/Introversion, Neuroticism,
Agreeableness, Consciousness, and Openness. There is an increasing recognition
that certain personality traits may render individuals vulnerable to psychiatric
disorders, including anxiety disorders and depression. Our purpose in this study
was to explore correlates between the personality dimensions neuroticism and
extraversion as assessed by the NEO Five-Factor Inventory (NEO-FFI) and
resting regional cerebral glucose metabolism (rCMRglu) in healthy control
subjects. Based on the anxiety and depression literatures, we predicted
correlations with a network of brain structures, including ventral and medial
prefrontal cortex (encompassing anterior cingulate cortex and orbitofrontal
cortex), insular cortex, anterior temporal pole, ventral striatum, and the
amygdala. Twenty healthy women completed an 18FFDG (18F-fluorodeoxyglu-
cose) positron emission tomography (PET) scan at rest and the NEO-FFI
inventory. We investigated correlations between scores on NEO-FFI Neuroti-
cism and Extraversion and rCMRglu using statistical parametric mapping
(SPM99). Within a priori search territories, we found significant negative
correlations between Neuroticism and rCMRglu in the insular cortex and
positive correlations between Extraversion and rCMRglu in the orbitofrontal
cortex. No significant correlations were found involving anterior cingulate,
amygdala, or ventral striatum. Neuroticism and Extraversion are associated
with activity in insular cortex and orbitofrontal cortex, respectively. Depression
and Anxiety 23:133–138, 2006. & 2006 Wiley-Liss, Inc.

Key words: neuroimaging; personality; neuroticism; extraversion

INTRODUCTION
P ersonality is a key concept in both psychology and
psychiatry. Personality typically refers to an integrated
pattern of thinking, feeling, and behaving that varies
among individuals but is stable within each individual
over time [Sugiura et al., 2000]. The Five-Factor
Model (FFM) of personality has recently emerged as
the dominant model of normal personality [Liveley,
2001]. According to the FFM, all the phenotypical
variation present in overt behavior can be explained by
five higher-order factors [Extraversion, Neuroticism,
Openness, Agreeableness, and Conscientiousness;
Goldberg, 1992]. Despite the ascendance of the FFM,
only two factors, Extraversion and Neuroticism, have
achieved near universal acceptance, whereas consider-
1
Department of Psychiatry, Massachusetts General Hospital,
Boston, Massachusetts
2
Neuroendocrine Unit, Massachusetts General Hospital,
Boston, Massachusetts
3
Division of Nuclear Medicine, Department of Radiology,
Massachusetts General Hospital, Boston, Massachusetts
Correspondence to: Thilo Deckersbach, Ph.D., Psychiatric
Neuroscience Division, Department of Psychiatry, Massachusetts
General Hospital/Harvard Medical School, Bldg. 149, 2611 13th
Street, Charlestown, MA 02129.
E-mail: tdeckersbach@partners.org
Received for publication 22 March 2005; Revised 20 July 2005;
Accepted 27 September 2005
DOI 10.1002/da.20152
Published online 7 February 2006 in Wiley InterScience (www.
interscience.wiley.com).

r 2006 Wiley-Liss, Inc.

134 Deckersbach et al.
able debate persists among theorist regarding the
importance, nature, and definition of the other three
of the factors [Depue and Lenzenweger, 2001].
Individuals scoring high on Extraversion are often
upbeat, optimistic, behaviorally active, and enjoy social
contact; they also report more positive emotions in
everyday life than do introverted individuals [McCrae
and Costa, 1999]. Individuals scoring high on Neuroti-
cism, on the other hand, worry frequently, often appear
anxious and apprehensive, and report more negative
emotions than individuals who score lower on Neuro-
ticism [McCrae and Costa, 1999].
In addition to being present in virtually all self-report
inventories, Neuroticism and Extraversion each have
high heritability, reaching up to .46 and .51, respec-
tively [Plomin and Caspi, 1999]. Extraversion is
considered to be the product of a behavior activating
system based on incentive motivation that functions to
facilitate positive reinforcement, whereas trait Neuro-
ticism is the expression of a behavior inhibiting system
based upon anxiety and harm avoidance [Depue and
Lenzenweger, 2001; Gray, 1992]. High trait levels of
Neuroticism and/or low Extraversion have been linked
to increased vulnerability to major depression and
anxiety [Watson and Clark, 1997].
Neuroimaging studies that explored the neurobiolo-
gical underpinnings of personality traits such as
Extraversion and Neuroticism have found associations
with brain structures that are known to be involved in
anxiety and affective disorders, including the amygdala
[Canli et al., 2002], subgenual prefrontal cortex [PFC;
Keightley et al., 2003], orbitofrontal cortex (OFC),
insular cortex [Johnson et al., 1999; Sugiura et al.,
2000], and temporal lobe [Turner et al., 2003]. For
example, Johnson et al. [1999], who conducted one of
the few cerebral blood flow (CBF) studies employing
the NEO-FFI (a short form the NEO Personality
Inventory—Revised [NEO-PI-R] that is frequently
used in personality research [Costa and McCrae,
1992]), found that Introversion was correlated with
blood flow in the lateral extent of the frontal cortex, the
insular cortex, and the right temporal cortex. Extra-
version was correlated with blood flow in the anterior
cingulate gyrus, right insular cortex, and bilateral
temporal lobes, as well as bilateral decreases in the
frontal lobe.
Given the prominence of Neuroticism and Extraver-
sion in the normal personality literature, the purpose of
this study was to explore the correlates of regional
cerebral glucose metabolism (rCMRglu) at rest with
the personality dimensions Neuroticism and Extraver-
sion as assessed by the NEO Five-Factor Inventory
[NEO-FFI; Costa and McCrae, 1992]. We utilized the
limited personality neuroimaging literature and the
more extensive anxiety and depression neuroimaging
literature to define a priori candidate brain regions that
may be associated with the personality dimensions
Neuroticism and Extraversion assessed by the NEO-
FFI. More specifically, limbic and paralimbic circuits
Depression and Anxiety DOI 10.1002/da
play an important role in mediating anxiety. These
include posterior medial orbitofrontal, anterior tem-
poral, anterior cingulate, and insular cortex (i.e.,
paralimbic cortex). These regions are linked with deep
limbic structures, such as the amygdala [Mesulam,
1985]. Contemporary models of threat assessment and
the normal fear response focus on the role of the
amygdala [Aggleton, 1992; LeDoux, 1996]. The func-
tions of the amygdala include preliminary threat
assessment, facilitation of fight-or-flight responses, as
well as enhancement of arousal and plasticity, so that
the organism can learn from the current experience to
guide responses in future similar situations. Conver-
sely, medial frontal cortex (i.e., anterior cingulate and
orbitofrontal cortex) provide important feedback to
and critical ‘‘top-down’’ governance over the amygdala
[Aggleton, 1992; LeDoux, 1996]. This includes the
medial frontal cortex (e.g., anterior cingulate and
orbitofrontal cortex), which appears to enable attenua-
tion of the fear response once danger has passed or
when the meaning of a potentially threatening stimulus
has changed. In addition, neuroimaging studies in
obsessive–compulsive disorder (OCD) have identified
abnormalities in the OFC and the striatum, and
posterior cingulate abnormalities may predict response
to treatment with fluvoxamine in OCD [e.g., Rauch
et al., 2002; Stein et al., 2000]. Likewise, there is
converging evidence implicating territories in the PFC
and temporal lobe structures in the pathophysiology of
major depression, including the anterior cingulate and
orbitofrontal cortex, as well as the amygdala [for a
review, see Davidson et al., 2002]. Based on these
findings, we hypothesized associations between NEO-
FFI Neuroticism and medial prefrontal cortex (including
subgenual and pregenual anterior cingulate cortex
[ACC]), posterior insulate cortex, insular cortex, tem-
poral pole, and amygdala). For NEO-FFI Extraversion,
we hypothesized associations with rCMRglu in the pre-
genual and subgenual ACC, ventral striatum, and OFC.
METHODS
Participants
Study participants were 20 normal volunteers (all
females; age: M 5 25.26, SD 5 3.66) recruited through
the Neuroendocrine Unit at the Massachusetts General
Hospital. Participants were without history of signifi-
cant head injury, seizure, neurological condition, or
current medical condition. Subjects were eligible to
participate in the protocol if they had no current or
past Axis I psychiatric disorder as confirmed by the
Structured Clinical Interview for DSM-IV [SCID;
First et al., 1995], and no psychotropic medication use
or hormonal therapy within the prior 6 months. These
individuals were recruited as healthy control partici-
pants for a study that compared rCMRglu in female
individuals with anorexia nervosa [Miller et al., 2004]
with that of normal control subjects. Participants had a
 Research Article: Glucose Metabolism Correlates of Personality
mean of 16 years’ education (M 5 16.47, SD 5 1.62)
and were of average or above average intelligence as
measured by the Wechsler Abbreviated Scale of
Intelligence (WASI; M 5 118.94, SD 5 10.50). Beck
Depression Inventory [BDI; Beck et al., 1961] scores
confirmed the absence of any substantial symptoms of
depression (M 5 1.21, SD 5 1.51). All subjects had
regular menstrual periods and were studied during
the early follicular phase (i.e., the first week) of their
menstrual cycles. The protocol was approved by the
Subcommittee on Human Studies at the Massachusetts
General Hospital, and written informed consent was
obtained from all subjects. All subjects completed an
18F
FDG (18F-fluorohydroxyglucose) positron emission
tomography (PET) scan at rest and the NEO-FFI
inventory. The NEO-FFI inventory was completed
before the PET scanning, prior to injection of the
radioactive tracer.
PET Image Acquisition and Analysis
18F
FDG (approximately 185 MBq, 5 mCI) was
injected intravenously in a quiet, dedicated waiting
room, where the subject was instructed to remain
sitting quietly, in accordance with a nominal ‘‘resting
state.’’ After a 45-min uptake period, the subject was
led to the adjacent imaging suite. After entering the
scanner, each subject was fitted with a thermoplastic,
custom-molded face mask to restrict head movements.
The subject was positioned within the PET camera so
that the head was aligned in the scanner relative to the
canthomeatal line. Emission data were acquired with
an HR1 PETcamera (CTI; Knoxville, TN), which has
an in-plane and axial resolution of 4.5 mm FWHM
(full width at half-maximum intensity), 63 contiguous
slices of 2.5 mm separation, and a sensitivity of
200,000 cps/microcurie/mL [two dimensional (2D)]
and 900,000 cps/microcurie/mL (3D).
The PET images were corrected for head movement
and transformed to the coordinate system developed
and distributed by the Montreal Neurologic Institute
(MNI) implemented in the SPM99 software package
(Welcome Department of Cognitive Neurology;
London). All images were smoothed and scaled using
a 15-mm FWHM 3D Gaussian filter. At each voxel the
PET data were normalized by the global mean and fit
to a linear statistical model by the method of least
squares. The scores for the NEO Neuroticism (NEO-
N) and NEO Extraversion (NEO-E) were incorpo-
rated as covariates of interest (correlational analysis).
Means (7standard deviations) for the NEO subscales
were as follows: Neuroticism, 40.30 (78.5); Extraver-
sion, 60.35 (79.18). The linear association between
rCMRglu and each personality dimension was tested
on a voxel-by-voxel basis using the SPM covariates
option. SPM t-statistics were transformed into SPM
z-scores. A priori defined regions of interest were
inspected first and were considered significant if at least
five contiguous voxels (kZ5) exceeded z 5 2.58
135
(P 5.005). A posteriori observed correlations were
considered statistically significant if at least five
contiguous voxels exceeded z 5 3.72 (P 5.0001). This
a posteriori significance threshold reflects the correc-
tion for multiple comparisons based on the number of
resolution units included in the whole search volume.
For correlations exceeding the statistical threshold in
the SPM analysis, we extracted data using MarsBaR
software creating spherical regions of interest (ROIs)
with a 2 mm diameter around the maximum voxel.
Data were then imported into SPSS software to
examine deviation from the normal distribution and
to search for outliers. Only correlations in which
statistical assumptions for correlational analysis were
met are reported. Locations of all statistically signifi-
cant correlations are reported using the 3D coordinates
of the MNI [x indicates right (1) or left ( ); y indicates
anterior (1) or posterior ( ); z indicates superior (1)
or inferior ( ) to the anterior commissure].
RESULTS
There were no significant correlations between age,
education, depression (BDI) and any of the personality
scores (all Ps4.10).
Neuroticism. Within our a priori search territory, a
significant negative correlation was observed between
NEO-N scores and rCMRglu in the left insular cortex
(r 5 .63, P 5.003; MNI: x 5 32, y 5 22, z 5 16; see
Fig. 1). A post hoc significant correlation between
NEO-N scores and rCMRglu was observed in the left
superior temporal gyrus [Brodmann’s area (BA22);
r 5 .77; Po.001; MNI: x 5 48, y 5 48, z 5 20].
Extraversion. A priori significant correlations be-
tween NEO-E scores and rCMRglu were observed for
two areas in the left and right OFC (BA11; left OFC:
r 5 .57, P 5.009; MNI: x 5 14, y 5 68, z 5 12; right
OFC: r 5 .63, P 5.001; MNI: x 5 20, y 5 18, z 5 12;
see Fig. 2).
No above threshold correlations were observed post
hoc in brain regions beyond those predicted a priori
with NEO-E scores.
DISCUSSION
We set out to explore correlations of the NEO-FFI
personality traits with rDMRglu. Consistent with our
a priori predictions, based on studies in healthy as well
as psychiatric samples, Neuroticism was correlated
with rCMRglu in the insular cortex. Extraversion was
correlated with glucose metabolism in the OFC. The
interpretation of these results principally relies upon
knowledge about the mediating anatomy of normal
emotional function. Likwise, whereas the implications
of these findings most directly relate to normal
personality, there is hope that these results will also
have implications for understanding personality traits
as vulnerability factors for developing psychiatric
diseases. Indeed, OFC and insular cortex are brain
Depression and Anxiety DOI 10.1002/da
136 Deckersbach et al.

40 The insular cortex, lying deep in the temporal lobe,

has been conceptualized mainly as viscerosensory
cortex. Electrical stimulation of the insular cortex in a
variety of mammals elicits changes in blood pressure,
30 heart rate, respiration, and gastrointestinal activity
[Cechetto and Chen, 1990]. Functional neuroimaging
(fMRI) studies have linked the anterior insula to
NEO_Neuroticism

attention and sensitivity to interoceptive cues as well

20
as the perceived aversiveness of stimuli [Critchley et al.,
2004; Jackson et al., 2005]. For example, Critchley and
colleagues [2004] found that anterior insular activation
10 (as assessed by fMRI) predicted how accurately
individuals judged their heart rate in a heartbeat
detection task. Jackson et al. [2005] found that insular
activation is associated with the degree to which
0 normal individuals perceive and assess social situations
50 60 70 80 as painful. This aspect of insular function may thus
INSULA rCMRglu contribute to Neuroticism as a personality trait
Figure 1. Scatterplot for the correlation between NEO- characterized as a proneness to worry frequently, be
Neuroticism scores and rCMRglu in the left insula (P o.005). anxious and apprehensive, and report more negative
emotions than individuals who score lower on Neuro-
ticism [McCrae and Costa, 2003]. Consistent with
Orbitofrontal Cortex(BA11) this view, increased insular activation has been reported
Left: x=-14, y=68, z=-12 Right: x=20,y=18, z=-12 in individuals with PTSD and/or animal phobia
[Liberzon et al., 1999; Wright et al., 2003]. In this
context, it is noteworthy to emphasize the distinction
between baseline insular activity as assessed by resting
FDG and insular activation (i.e., change in activity level
between two conditions, as assessed with cognitive
activation paradigms). Neuroticism may be associated
with increased insular activation, because these indivi-
duals might be hypersensitive to interoceptive cues,
thereby enhancing susceptibility to anxiety states.
Therefore, it is possible that individuals with lower
baseline levels of activity in this region may be more
sensitive to these minor changes in interoceptive
signals, thereby accounting for the negative correlation
between NEO-N and resting insular activity (as
assessed by FDG in the present study). To further
explore this possiblity, it would be valuable to assess the
50
A
50
B
relationship between personality traits and regional
brain activity (e.g., resting FDG) as well as activation
NEO Extraversion

NEO Extraversion

40 40 (e.g., change in rCBF) in the same subjects.

30
20
42 44 46 48 50 52 54 56 58
OFC rCMRglu
Figure 2. Correlations between NEO-Extraversion scores and
rCMRglu in the orbitofrontal cortex (P o.005) in the left
orbitofrontal cortex (A) and right orbitofrontal cortex (B) OFC
superimposed on averaged MRIs.
regions that have been implicated in various psychiatric
disorders, including anxiety (e.g., OCD, posttraumatic
stress disorder [PTSD]), and affective disorders (in-
cluding major depressive and bipolar disorders).
Depression and Anxiety DOI 10.1002/da
We also found a correlation between Extraversion
30 and rCMRglu in the ventromedial prefrontal cortex.
This finding is largely consistent with the results of a
20 previous study [Johnson et al., 1999] that investigated
66 68 70 72 74 76 78 80 82 the correlation between rCBF and Extraversion.
OFC rCMRglu
However, it should be noted, that Johnson et al. found
a negative correlation between rCBF and Extraversion
and that the locus (BA11) was slightly more lateralized
than the areas of correlations in the OFC found in our
study. It is possible that differences in imaging
modalities (blood flow vs. rCMRglu) or sample
differences may account for this disparity in findings.
Specifically, our sample consisted exclusively of female
participants, whereas that of Johnson et al. included
male and female participants. Thus, caution is advised
when extrapolating from our sample of exclusively
 Research Article: Glucose Metabolism Correlates of Personality
female participants to male individuals. Replication and
extension of our findings in mixed and/or male samples
are warranted. The ventromedial PFC, including the
OFC, among other brain structures, is believed to play
a crucial role in inhibitory functions [e.g., Davidson
et al., 2000]. Functional neuroimaging studies that used
emotion induction paradigms have commonly found
that the ventral prefrontal cortex is recruited during
anger states [e.g., Blair et al., 1999; Damasio et al.,
2000]. PET FDG studies have demonstrated that
patients with impulsive aggression, unlike healthy
individuals, do not show rCMRglu increases of the
ventromedial prefrontal cortex in response to admin-
istration of fenfluramine [Siever et al., 1999; Soloff
et al., 2000] or metachlorophenylpiperazine [New
et al., 2002]. These findings support the view that that
the ventral PFC plays a crucial role in constraining
impulsive acts or behaviors [Davidson et al., 2000]. Our
study extends these findings by suggesting that OFC
metabolism at rest may reflect not only psychiatric
pathology but also interindividual differences in
personality traits (i.e., Extraversion) in normal indivi-
duals. In healthy individuals, the OFC appears to
mediate autonomic responding [Critchley et al., 2000],
in particular, skin conductance, in the service of
guiding motivational behavior and decision making.
Studies in both animals and humans have shown OFC
involvement in processes supporting stimulus–reward
reversal, monitoring the incentive value of reinforcers,
and reward-based decision making [Cohen et al., 2005;
Cox et al., 2005; Dias et al., 1997; Gallagher et al.,
1999; Remijnse et al., 2005]. For example, OFC
activity occurs early in the context of discrimination
tasks, suggesting that animals are using anticipated
outcomes in order to guide current goal-directed
behavior [Lipton et al., 1999; Schoenbaum et al.,
1998]. In addition, ventral PFC activity is critical to
extinction retention [see Phelps et al., 2004]. Thus,
with respect to reward, higher OFC metabolism may
shift peoples’ orientation toward external positive
reinforcers (i.e., increased insensitive motivation). On
the other hand, those people with optimally developed
ventral PFC function may be able to best qualify their
fear learning to circumscribed genuinely dangerous
events, and therefore be open to activities of modest
risk. This conceptualization is consistent with the
current finding of positive correlation between NEO-E
and resting metabolism within OFC.
Besides correlations between NEO and glucose
metabolism in the insula and OFC, our study was
characterized by a notable absence of correlations in
several a priori predicted brain regions. These include
the ACC, amygdala, and the striatum. It should be
noted that our study had sufficient statistical power to
detect only large correlations (rZ.65), and it is possible
that correlations between Neuroticism, Extraversion,
and resting glucose metabolism in the ACC, amygdala,
and striatum were below the statistically defined
threshold. It is possible (and likely) that regions such
137
as the ACC, amygdala, and striatum participate in
functions relevant to personality traits such as Neuroti-
cism or Extraversion. However, it may be that
associations of smaller effect went undetected due to
these power constraints. In general, effects based on
intersubject correlations may be more pronounced in
studies that include individuals with psychopathology
as well as healthy controls. Alternatively, it may be that
resting metabolic activity is not the most salient
measure for detecting their relevant roles. For instance,
measures of responses (condition-related changes in
activity) may be critical to appreciating their participa-
tion in the networks that mediate these personality
traits. Consequently, future studies should employ
paradigms to test for relationships between activation
of the amygdala, striatum, and ACC, and Neuroticism
and Extraversion. More specifically, such tasks might
include those that entail responses to threat-related or
novel stimuli [amygdala; e.g., Schwartz et al., 2003;
Whalen et al., 2004], reward [ventral striatum; e.g.,
Delgado et al., 2005], and attention/response suppres-
sion, error monitoring, or reward-based decision
making [ACC; e.g., Bush et al., 2002; Holroyd et al.,
2004; Williams et al., 2004].
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