PS YC HOLOGICA L SC IENCE
Short Report
Changes in Anterior Cingulate
and Amygdala After Cognitive
Behavior Therapy of
Posttraumatic Stress Disorder
Kim Felmingham,1,2 Andrew Kemp,1,2 Leanne Williams,1,2 Pritha Das,1,3 Gerard Hughes,1,4
Anthony Peduto,1,4 and Richard Bryant1,5
1
Brain Dynamics Centre, Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia;
Division of Psychological Medicine, Western Clinical School, University of Sydney, Camperdown, New South Wales,
Australia; 3Neuroscience Institute of Schizophrenia and Allied Disorders, Darlinghurst, New South Wales, Australia;
4
MRI Unit, Department of Radiology, Westmead Hospital, Westmead, New South Wales, Australia; and 5School of
Psychology, University of New South Wales, Kensington, New South Wales, Australia
2
Posttraumatic stress disorder (PTSD) may develop from impaired extinction of conditioned fear responses. Exposure-based
treatment of PTSD is thought to facilitate extinction learning
(Charney, 2004). Fear extinction is mediated by inhibitory
control of the ventromedial prefrontal cortex (vmPFC) over
amygdala-based fear processes (Phelps, Delgado, Nearing, &
LeDoux, 2004; Quirk, Russo, Barron, & LeBron, 2000). Most
neuroimaging studies of PTSD reveal reduced vmPFC activity
(particularly in rostral anterior cingulate cortex, or rACC;
Lanius et al., 2001; Shin et al., 2005), and some find increased
amygdala activity during threat processing (Shin et al., 2005). In
addition, increased amygdala activity during fear conditioning
and reduced vmPFC activity during extinction have been reported in PTSD (Bremner et al., 2005).
Although PTSD patients show increased orbitofrontal and
medial prefrontal activity following treatment with serotonin
reuptake inhibitors (SSRIs; Fernandez et al., 2001; Seedat et al.,
2004), no studies have investigated neural networks before and
after exposure-based treatment of PTSD. We report the first such
study. We hypothesized that symptom reduction would be associated with increased rACC activity and reduced amygdala
activity during fear processing.
Address correspondence to Kim Felmingham, Brain Dynamics Centre, Westmead Hospital, Westmead, NSW 2145, Australia, e-mail:
[email protected].
Volume 18—Number 2
METHOD
Eight individuals (5 females) with PTSD following assault (n 5
4) or car accidents (n 5 4) were recruited from the Westmead
PTSD Unit, New South Wales, Australia. Average time post
trauma was 65 months (SD 5 64.0), and the subjects’ mean age
was 36.8 years (SD 5 8.8). Subjects were assessed using the
Clinician-Administered PTSD Scale (CAPS; Blake et al., 1990)
and the Structured Clinical Interview for DSM-IV Axis 1 Disorders (First, Spitzer, Gibbon, & Williams, 1997). Four subjects
had comorbid major depression. Two subjects were medicated
with SSRIs during the period when the testing sessions took
place. Subjects were excluded if they had a history of neurological condition, psychosis, borderline personality disorder, or
substance abuse. After giving informed written consent, participants received eight once-weekly sessions of imaginal exposure and cognitive restructuring (Bryant, Moulds, Guthrie,
Dang, & Nixon, 2003). Patients underwent scanning prior to and
6 months following treatment.
Magnetic resonance imaging (MRI) scans were performed on
a 1.5-T Siemens Vision Plus Scanner using an echoplanar protocol. Subjects viewed 120 fearful and 120 neutral standardized
facial expressions (Gur et al., 2002) presented in a pseudorandom sequence of 30 blocks (8 fearful faces and 8 neutral
faces per block). Stimuli were presented for 500 ms, with a
768-ms interstimulus interval. Ninety functional T n 2-weighted
volumes were acquired (6.6 mm thickness; time of repetition,
Copyright r 2007 Association for Psychological Science
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Neural Activity and Posttraumatic Stress Disorder
TR 5 3.3 s; echo time, TE 5 40 ms; flip angle 5 901; field of
view, FOV: 24 24 cm2; matrix size: 128 128). Preprocessing
and statistical analysis of blood-oxygenation-level-dependent
(BOLD) data were conducted using SPM2.
BOLD signal change was based on the contrast between responses to fearful and neutral faces in a repeated measures
fixed-effects analysis of variance. We used region-of-interest
(ROI) analyses for anterior cingulate cortex (ACC) and amygdala to test our a priori hypotheses. ROIs were defined by the
automated anatomical labeling masks (Tzourio-Mazoyer et al.,
2002). The statistical thresholds employed were p < .05 (smallvolume corrected) for ROI analyses and p < .001 for whole-brain
analyses. BOLD signal change was correlated with change in
total CAPS score from before to after treatment, and the statistical threshold for this analysis was p < .01.
RESULTS
Treatment Outcome
The mean CAPS score was 78.1 at pretest (SD 5 20, range:
55–120) and was reduced to 28.9 at posttest (SD 5 20.3, range:
2–52). All subjects revealed at least a 30% reduction in total
CAPS score.
MRI
The ROI analyses revealed significantly greater activation in
bilateral rACC after treatment than before treatment, left
hemisphere: t(7) 5 2.03, p 5 .021 (Montreal Neurological Institute, MNI, coordinates: x 5 4, y 5 52, z 5 2; 10 voxels),
right hemisphere: t(7) 5 1.79, p 5 .036 (x 5 4, y 5 44, z 5 0; 36
voxels). There were no significant activations in amygdala before or after treatment. Whole-brain analysis revealed significantly greater activation before than after treatment in right
postcentral gyrus, t(7) 5 4.18 (x 5 66, y 5 16, z 5 32; 172
voxels); right middle temporal gyrus, t(7) 5 3.59 (x 5 50, y 5
62, z 5 6; 29 voxels), and left superior temporal gyrus, t(7) 5
3.48 (x 5 60, y 5 4, z 5 4; 41 voxels). In contrast, activation
was greater after than before treatment in left middle temporal
gyrus, t(7) 5 3.94 (x 5 52, y 5 18, z 5 12; 213 voxels);
right inferior frontal gyrus, t(7) 5 3.75 (x 5 60, y 5 26, z 5 2; 57
voxels); left parietotemporal gyrus, t(7) 5 3.74 (x 5 56, y 5
62, z 5 32; 47 voxels); and right hippocampus, t(7) 5 3.23,
p 5 .001 (x 5 34, y 5 24, z 5 12; 6 voxels).
A significant positive correlation was found between change
in total CAPS score and change in right rACC activity (x 5 8,
y 5 36, z 5 8) from before to after treatment (r 5 .84, p < .01; see
Fig. 1). A negative correlation was found between activation in
bilateral amygdala (x 5 18, y 5 4, z 5 16) and change in total
CAPS score (r 5 .85, p < .01; see Fig. 1). Therefore, as CAPS
scores improved, rACC activity increased and amygdala activity
decreased during fear processing.
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Fig. 1. Correlation between changes in blood-oxygenation-level-dependent (BOLD) activity and changes in total severity of posttraumatic
stress disorder (i.e., changes in total score on the Clinician-Administered
PTSD Scale, or CAPS) following exposure-based treatment. The functional maps display the areas where changes in BOLD activity in anterior
cingulate cortex (ACC) and amygdala (AMG) correlated with changes in
total CAPS score; the color scale represents the strength of the correlation. The scatter plots display the direction of these correlations (improvement on total CAPS on the horizontal axis, extent of BOLD activity
on the vertical axis).
DISCUSSION
This study provides the first evidence that successful exposure
therapy for PTSD is associated with increased rACC and reduced amygdala activation during fear processing. This pattern
is consistent with evidence of vmPFC involvement in fear extinction (Quirk et al., 2000). This study requires replication in
research using larger samples, employing a wait-list control
condition, and examining responses to trauma-related stimuli.
The current data indicate that the neural correlates of fear
processing after improvement in PTSD symptoms accord with
evidence that amygdala and rACC activity underlie the acquisition and extinction of conditioned fear.
Acknowledgments—This research was supported by a National Health and Medical Research Council (NHMRC)
Program Grant (300304), an Australian Research Council
Linkage Grant (LP0212048), an NHMRC Peter Doherty
Fellowship (358770), and an NHMRC Australian Clinical
Research Fellowship (358676).
Volume 18—Number 2
K. Felmingham et al.
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(RECEIVED 2/2/06; REVISION ACCEPTED 7/3/06;
FINAL MATERIALS RECEIVED 8/24/06)
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