Journal of Anxiety Disorders 25 (2011) 251–257
Contents lists available at ScienceDirect
Journal of Anxiety Disorders
Differential activity of subgenual cingulate and brainstem in panic disorder
Oliver Tueschera,c,d,∗,1, Xenia Protopopescua,b,1, Hong Pana,j, Marylene Cloitree, Tracy Butlera,
Martin Goldsteina,f, James C. Roota, Almut Engeliena,g, Daniella Furmana, Michael Silvermana,f,
Yihong Yanga, Jack Gormani, Joseph LeDouxh, David Silbersweiga,j, Emily Sterna,j
aFunctional Neuroimaging Laboratory, Department of Psychiatry, Weill Medical College of Cornell University, United States
bThe Rockefeller University, Laboratory of Neuroendocrinology, United States
cDepartment of Psychiatry and Psychotherapy, Albert-Ludwigs University, Freiburg, Germany
dDepartment of Psychiatry and Psychotherapy, Johannes Gutenberg University, Mainz, Germany
eNYU Child Studies Center, New York University School of Medicine, United States
fMount Sinai School of Medicine, United States
gDepartment of Psychiatry and IZKF Münster, University of Münster, Germany
hCenter for Neural Science, New York University, United States
iComprehensive NeuroScience, Inc., White Plains, New York, United States
jDepartment of Psychiatry, Brigham & Women’s Hospital, Harvard Medical School, Boston, United States
a r t i c l e i n f o
Received 17 June 2010
Received in revised form 25 August 2010
Accepted 10 September 2010
Posttraumatic stress Disorder
Subgenual cingulate cortex
a b s t r a c t
Most functional neuroimaging studies of panic disorder (PD) have focused on the resting state, and have
explored PD in relation to healthy controls rather than in relation to other anxiety disorders. Here, PD
patients, posttraumatic stress disorder (PTSD) patients, and healthy control subjects were studied with
functional magnetic resonance imaging utilizing an instructed fear conditioning paradigm incorporat-
ing both Threat and Safe conditions. Relative to PTSD and control subjects, PD patients demonstrated
significantly less activation to the Threat condition and increased activity to the Safe condition in the
subgenual cingulate, ventral striatum and extended amygdala, as well as in midbrain periaquaeductal
grey, suggesting abnormal reactivity in this key region for fear expression. PTSD subjects failed to show
the temporal pattern of activity decrease found in control subjects.
© 2010 Elsevier Ltd. All rights reserved.
Panic disorder (PD) and posttraumatic stress disorder (PTSD)
are anxiety disorders with evolving neurocircuitry models. Bio-
logical studies of anxiety disorders have focused on comparisons
between patient groups and healthy controls, with only one neu-
roimaging study to date directly comparing PD and PTSD (Lucey
et al., 1997). This resting state (single photon emission computed
tomography, SPECT) study found significant cerebral blood flow
and right caudate nuclei. However, to develop disorder-specific
∗Corresponding author at: Functional Brain Imaging, Department of Psychia-
try and Psychotherapy, Albert-Ludwigs-University, Breisacher Strasse 64, D-79106
Freiburg, Germany. Tel.: +49 761 270 5232; fax: +49 761 270 5416.
E-mail address: email@example.com (O. Tuescher).
1Both authors contributed equally to this work.
of the differences in the underlying dysfunctional neurocircuitries
in these disorders is required. Neurobehavioral and neurocircuitry
prefrontal hypoactivity to external threat (Milad, Rauch, Pitman,
& Quirk, 2006) whereas panic disorder appears to be marked by
internally generated threat (Lissek et al., 2009) driven by dysfunc-
tional ventromedial prefrontal (ACC), amygdalar and brainstem
regions (Graeff & Del-Ben, 2008). Core components of panic disor-
der include autonomic signs like increased respiration, heart rate,
and blood pressure which are modulated by key regions in the
basal forebrain and the brainstem. The medial frontal cortical net-
work (including Brodmann area 25) provides a major output to the
hypothalamus and brain stem and contributes to this visceromotor
system (Price, 1999). The ventral striatum, known for its central
role in reward processing is implicated in coding emotional inten-
sity and self-relatedness of a variety of stimuli, independent of
their valence (Phan et al., 2004). The bed nucleus of the stria termi-
anxiety (Davis & Shi, 1999).
0887-6185/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
O. Tuescher et al. / Journal of Anxiety Disorders 25 (2011) 251–257
Primary diagnosisAge Gender Secondary diagnosis
Generalized anxiety disorder (GAD), past Major depressive disorder (MDD)
Social phobia, agoraphobia
GAD, specific phobia, personality disorders (avoidant, obsessive compulsive, and paranoid)
Mild MDD, GAD (subthreshold)
Social phobia, specific phobia, OCD, dysthymia
Binge eating disorder
Past EtOH dependence, past substance induced mania
Past MDD, past EtOH and substance dependence
Several studies have explored systemic pathophysiologic dif-
ferences between PD and PTSD. PTSD and PD patients may have
distinct profiles with respect to cortisol levels and hypothalamic-
2007); polysomnography (Sheikh, Woodward, & Leskin, 2003);
heart rate variability (Cohen et al., 2000), genetic contributions
(Skre, Onstad, Torgersen, Lygren, & Kringlen, 1993); and acquisi-
tion of conditioned fear-potentiated startle to learned safety and
danger cues (Lissek et al., 2009). A study utilizing eyeblink elec-
tromyography, heart rate, and skin conductance responses (SCR)
a decrease in response probability and a decrease in the SCR in
PD, but not in PTSD (Shalev, Bloch, Peri, & Bonne, 1998). Since
both diseases share key symptoms (e.g. panic attacks) and both are
thought to be elicited by abnormal fear conditioning/fear learning
(Gorman, Kent, Sullivan, & Coplan, 2000; Phelps & LeDoux, 2005)
direct experimental comparison can help to differentiate the neu-
robiological underpinnings of both diseases and give direction to
specific therapeutic targets.
In this study, we used functional magnetic resonance imaging
(fMRI) to compare neural responses in PD patients relative to PTSD
patients and healthy comparison subjects during an instructed fear
paradigm consisting of a Threat and a Safe condition (Butler et al.,
2007; Phelps et al., 2001). In this task, the association of a previ-
ously neutral stimulus with a possible aversive event is learned by
means of a verbal instruction given before the start of the scan.
Symbolically acquired fear results in physiological fear responses
conditioned stimulus and its extinction in classical fear condition-
Fig. 1. (A) Coronal (y=−5), axial (z=−12), and sagittal (x=0) sections showing increased amygdala activity and subgenual cingulate (Brodmann area 25) activity in early
runs (parametric modeling of the Threat vs. Safe by Early vs. Late interaction) in Normal Control subjects (p<0.01). (B) The bar plot shows the in BOLD response±SD (%) at
the point showing maximum activity for the Threat vs. Safe by Early vs. Late interaction in the amygdala (MNI [−21, 0, −12]). BOLD response is shown for Normal Controls,
conditions [Threat, Safe], and study session [broken into Early and Late run] relative to a resting baseline.
O. Tuescher et al. / Journal of Anxiety Disorders 25 (2011) 251–257
Fig. 2. (A) Coronal (y=0 and y=6), and sagittal (x=6) sections showing decreased subgenual cingulate (Brodmann area 25), ventral striatum, and extended amygdala activity
for the Threat vs. Safe condition in Panic vs. PTSD subjects (p<0.01). (B) The bar plot shows BOLD response±SD (%) at the point showing maximum activity for the Threat vs.
Safe condition in Panic vs. PTSD subjects [6, 12, −9]. This point is located in the subgenual anterior cingulate cortex. BOLD response is shown for groups [Panic, PTSD, Normal
Controls], conditions [Threat, Safe], and study session [broken into Early and Late run] relative to a resting baseline.
ing (Butler et al., 2007; Phelps et al., 2001). Based on Butler et al.
involved in fear processing, i.e. medial prefrontal, insula, ventral
striatal, amygdalar and brainstem, would exhibit increased activ-
ity for Threat vs. Safe conditions and would habituate over time in
a subset of those regions (Butler et al., 2007). For PTSD subjects, we
hypothesized that these same regions would not exhibit habitua-
tion from early to late runs of the experimental paradigm. For PD
subjects, we hypothesized that these same regions would exhibit
abnormal reactivity to the (external) Threat and Safe conditions.
Participants were 8 subjects meeting DSM-IV criteria for PD
(mean age=37 years, range=24–50); 8 subjects meeting DSM-
IV criteria for PTSD (mean age=42 years, range=37–50); and 8
healthy comparison subjects (mean age=35 years, range=24–49).
PTSD and comparison subjects were a matched subset of larger
groups. Each group consisted of 4 female and 4 male right-
O. Tuescher et al. / Journal of Anxiety Disorders 25 (2011) 251–257
Interaction contrast PD vs. PTSD×Threat vs. Safe.
Brain regionMNI coordinates x, y, zZ-value
p-value SVC corr
Relative increased activity
Dorsal midbrain/mesial periaquaeductal grey
Relative decreased activity
Subgenual cingulated, ventral striatum, and extended amygdala
6, −24, −18
9, 12, 3
6, 12, −9
diagnoses of generalized anxiety disorder, social phobia, specific
phobia, major depressive disorder, dysthymia, and personality dis-
orders (Table 1). Otherwise, all participants were free of other
psychiatric diagnoses, substance abuse, and significant neuro-
logical or medical disorders. No subjects were on psychiatric
medication, except one PD subject (sertraline, bupropion). Written
with an IRB-approved protocol.
1.2. Experimental paradigm
stimulation to be received during the scan via a standardized dial-
up procedure to a level of intensity experienced as “uncomfortable
but not painful” to standardize subjective stimulus aversiveness
across subjects. The scanning session consisted of a “Threat”
condition, about which participants were told “an electroder-
mal stimulation can occur at any time”, and a “Safe” condition
during which participants were told they would receive no stimu-
lations. Threat and Safe were signified by the presentation of easily
distinguishable colored squares via an MR-compatible screen. Pre-
sentation of stimuli was controlled by the Integrated Functional
Imaging System (Invivo, Orlando, FL) using E-prime software (Psy-
chology Software Tools, Pittsburgh, PA). Pairing of colors with
conditions was counterbalanced across participants. Each color
appeared for a period of 12s followed by a 18s rest period. There
were five pseudo-randomly ordered blocks of each color per scan-
ning run, and two scanning runs (first run=early run; second
run=late run) per study session. Participants did not receive any
electrodermal stimulation during scanning.
1.3. Image acquisition
Gradient echo echo-planar functional images (TR=1200;
TE=30; flip angle=70◦; FOV=240mm; fifteen 5mm slices; 1mm
interslice gap; matrix=64×64) sensitive to blood oxygen level-
dependent (BOLD) signal were obtained with a GE-Sigma 3T MRI
scanner. Images were acquired using a modified z-shimming algo-
rithm to minimize susceptibility artifact at the base of the brain
(Gu et al., 2002). An identically sliced reference T1 weighted
anatomical image was acquired to aid re-orientation and co-
registration. A high-resolution T1 weighted anatomical image was
acquired using a spoiled gradient recalled acquisition sequence
(TR/TE=30/8ms, flip angle=45, FOV=240mm, 100 1.5mm axial
1.4. Image processing and data analysis
of EPI images to correct for slight head movement between scans
and for differential spin excitation history based on intracranial
voxels; extraction of physiological fluctuations such as cardiac and
respiratory cycles from the EPI image sequence (Frank, Buxton,
& Wong, 2001); co-registration of functional EPI images to the
corresponding high-resolution anatomical image based on the
rigid body transformation parameters of the reference anatomical
image to the latter for each individual subject; stereotactic nor-
malization to a standardized coordinate space (Montreal MRI Atlas
version of Talairach space) based on the high-resolution anatom-
ical image; spatial smoothing with an isotropic Gaussian kernel
Using customized fmristat software (Worsley et al., 2002),
a two-stage voxel-wise linear mixed-effects model was utilized
to examine the key Group/Condition contrasts of interest. First,
a whole-brain voxel-wise multiple linear regression model was
employed at the individual subject level which comprised the
regressor of interest, the covariates of no interest (the first-order
temporal derivative of the regressor of interest, global and phys-
iological fluctuations, realignment parameters, scanning period
means, and baseline drift up to the third order polynomials) and
an AR(1) model of the residual time series to accommodate tem-
poral correlation in consecutive scans. Second, at the group level, a
drawn. Age and gender were used as covariates of no interest in an
analysis of covariance setting.
A voxel-wise inference at the group level was then drawn
according to Gaussian random field theory. Initial uncorrected
threshold was p<0.001; comparisons were considered significant
at p<0.05 in either whole brain correction or in small volume
correction in a priori regions of interest (amygdala, basal ganglia
and vmPFC) selected based on previous results (Butler et al., 2007;
activity t-maps are shown at voxel-wise p-values less than 0.01 for
the purpose of presentation only.
During debriefing all subjects indicated that they had expected
to receive an electrodermal stimulation during the presentation of
the Threat stimulus and that this expectation was associated with
the feeling of fear which decreased with repeated presentations
In healthy control subjects significant activation was exhibited
in the contrast of Threat versus Safety in bilateral anterior insula,
bilateral basal ganglia and thalamus, bilateral dorsal anterior cin-
gulate and bilateral dorsolateral prefrontal cortex (Butler et al.,
2007). In the contrast of Safe versus Threat, increased activation
was found in bilateral primary motor cortex, bilateral hip-
pocampi/parahippocampi, bilateral posterior cingulate/precuneus
and angular gyri as well as in bilateral medial and lateral
orbitofrontal cortex from a larger sample (Butler et al., 2007). Pre-
vious studies have shown an attenuation of amygdalar activity and
relative decrease followed by an increase of vmPFC/sgACC activity
over time (Butler et al., 2007; Phelps et al., 2004, 2001). Paramet-
ric modelling of trials over time revealed an initial decrease of
amygdalar activation (Fig. 1A; cp. Butler et al., 2007) which was
mainly driven by the Threat condition (Fig. 1B) and accompanied
by a co-variation in sgACC activity (Fig. 1A).
O. Tuescher et al. / Journal of Anxiety Disorders 25 (2011) 251–257
Fig. 3. (A) Coronal (y=12), axial (z=−17), and sagittal (x=−8) sections showing increased dorsal midbrain/mesial periaquaeductal grey and (right) caudate for the Threat vs.
Safe by Early vs. Late interaction in Panic vs. PTSD subjects (p<0.01). (B) The bar plot shows BOLD response±SD (%) at the point showing maximum activity for the Threat
vs. Safe by Early vs. Late interaction in Panic vs. PTSD subjects MNI [6, −24, −18]. This point is located in the tegmental periaqueductal gray area. BOLD response is shown for
groups [Panic, PTSD, Normal Controls], conditions [Threat, Safe], and study session [broken into Early and Late run] relative to a resting baseline.
less activation in the Threat versus Safe contrast in regions includ-
ing the subgenual cingulate (Brodmann area 25), ventral striatum,
and extended amygdala, with contrast maximum in the subgenual
rected]; Fig. 2A, Table 2). These findings were due to an increase in
activation to the Safe condition in PD patients, co-varying with an
increased activity to the Threat condition in PTSD patients (Fig. 2B).
When the study sessions were broken into Early (first run) and Late
(second run) components, healthy control subjects activated this
O. Tuescher et al. / Journal of Anxiety Disorders 25 (2011) 251–257
region most strongly in the Early Threat condition while PTSD sub-
jects activate this region equivalently in the Early and Late Threat
conditions (Fig. 2B).
The direct contrast of Early (first half) and Late (second
half) components of the Threat versus Safe comparison revealed
increased activity in PD versus PTSD patients, most prominently
in the dorsal midbrain/mesial periaquaeductal grey (MNI [6, −24,
−18], Z=4.49, voxel-wise p<0.0001, p<0.003 [corrected]; Fig. 3A;
Table 2) and right caudate (MNI [9, 12, 3], Z=3.72, voxel-wise
p<0.0001, p<0.045 [corrected]; Fig. 3A; Table 2). Inspection of
the BOLD responses in the dorsal midbrain/mesial periaquaeduc-
tal grey (MNI [6, −24, −18]; Fig. 3B) revealed a time-by-condition
interaction in PD patients with a marked response to the late Safe
Using cognitively instructed fear, this study demonstrates sig-
nificantly less activation to threat cues and increased activity to
safety cues in the subgenual cingulate, ventral striatum, extended
amygdala and midbrain periaquaeductal grey in PD patients, sug-
gesting abnormal reactivity in these regions for fear expression.
PTSD subjects, in comparison, failed to show the temporal pattern
of activity decrease found in control subjects.
motor, autonomic, and emotional circuitry (Price, 1999), decreased
tral striatum in the Threat versus Safe contrast in PD versus PTSD
patients is notable. This same network appears to be activated
in healthy control subjects under the most threatening condi-
tion (Early Threat), and in PTSD subjects fails to habituate over
time under threat conditions, supporting models of failure of PTSD
patients to habituate to threatening stimuli (Protopopescu et al.,
Studies in rats and humans have shown that the medial pre-
frontal cortex plays a critical role in the retention and expression
of extinction memory (Milad et al., 2006; Morgan, Romanski, &
LeDoux, 1993), with subgenual cingulate cortex specifically medi-
ating successful extinction learning and retention (Phelps et al.,
2004). Deficits in fear extinction have been hypothesized to play
a central role in PTSD (Milad et al., 2006), and such deficits have
recently been demonstrated in psychophysiologic studies of PTSD
(Blechert, Michael, Vriends, Margraf, & Wilhelm, 2007) as well as
PD (Michael, Blechert, Vriends, Margraf, & Wilhelm, 2007). Our
results complement these findings that PTSD and PD might, in
part, be related to deficits in extinction learning subserved by the
same neuroanatomical region (subgenual cingulate) but by differ-
ent functional/neuronal mechanisms (cp. Fig. 2B). While Normal
Control subjects show strong ventromedial prefrontal cortex activ-
ity in the Early Threat condition alone, PTSD subjects show weaker
ventromedial prefrontal cortex activity which persists across the
Early and Late Threat conditions.
The increased activation of the medial frontal cortical network
and, in the late phase, the brainstem to the Safe condition in PD
patients (a reversal of the activation pattern seen in PTSD patients
and healthy controls) is particularly interesting and is intriguingly
in-line with recent behavioral evidence for an impairment of dis-
crimination learning in PD (Lissek et al., 2009) which might reflect
nation for this finding is that unlike PTSD, in which dysfunction
is related to external threat, PD is largely concerned with inter-
nal viscero-somatic threat, possibly generated in the brainstem
(Gorman et al., 2000; Protopopescu et al., 2006).
The ventromedial prefrontal cortex and brainstem findings in
this study are especially interesting in light of a recent fMRI
study demonstrating that threat imminence elicits a prefrontal-
periaqueductal gray shift in humans (Mobbs et al., 2007). This
study used electrodermal “shock” stimuli in concert with a vir-
tual predator maze task, and showed that activity in the (mesial)
periaquaeductal gray correlated with increased subjective sense
of dread and decreased confidence of escape (Mobbs et al., 2007).
Conversely, in the same study, decreased dread and increased con-
fidence of escape was associated with increased activity in the
ventromedial prefrontal cortex. In the current study, PD subjects
in the Early Threat (strongest external threat) condition activated
the brainstem but not the ventromedial prefrontal cortex (in line
with the Mobbs findings on “imminent threat”). This contrasts
with the healthy control subjects who activated ventromedial
tion. PD subjects in the Late Safe condition (perhaps the strongest
internal visero-somatic threat condition as it is the farthest from
task defined external threat) demonstrated their strongest brain-
stem and ventromedial prefrontal cortex activations, in contrast to
in these regions in this Late Safe condition.
One limitation of this study is that a subset of PD and PTSD
subjects had a range of psychiatric comorbidities, typical in most
PD and PTSD diagnosed individuals, and reflecting an overlap of
clinical and likely biological features. However, no systematic dis-
parity in comorbid diagnoses was present between groups, making
and group-specific activity in the hypothesized regions was exhib-
ited despite those comorbidities in a mixed-effects model that is
considered statistically more stringent and capable of addressing
inter- and intrasubject variability and generalizable to the larger
population. The same line of arguments holds true for another
issue to consider, namely the current medication of one PD sub-
ject. Yet another limitation is the small number of participants in
To mitigate this limitation, subjects were matched across groups
as closely as possible and, as above, a mixed-effects model was
used to address inter- and intrasubject variability and to improve
generalizability to the general population. Nevertheless, it will be
important in the future to conduct studies with additional patients
and larger sample sizes, to extend and test the replicability of these
These findings contribute to the growing literature examining
the potentially unique neurocircuitry subserving distinct anxiety
disorders. Key findings in the present study may suggest a height-
ened sensitivity to internally generated, viscerosomatic threat in
PD versus heightened sensitivity to external threat in PTSD, as
well as to impaired discrimination learning in PD versus impaired
extinction learning in PTSD on the behavioral level. Neuroimaging
studies contributing to the characterization of more specific patho-
physiological mechanisms underlying PD and PTSD may identify
diagnostically and therapeutically relevant biomarkers.
Funding for this study was provided by the NIMH Grant P50
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