Quantitative meta-analysis of neural activity in posttraumatic stress disorder. Biol Mood Anxiety Disord 2:9

Article (PDF Available)inBiology of Mood and Anxiety Disorders 2(1):9 · May 2012with56 Reads
DOI: 10.1186/2045-5380-2-9 · Source: PubMed
Abstract
In recent years, neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have played a significant role in elucidating the neural underpinnings of posttraumatic stress disorder (PTSD). However, a detailed understanding of the neural regions implicated in the disorder remains incomplete because of considerable variability in findings across studies. The aim of this meta-analysis was to identify consistent patterns of neural activity across neuroimaging study designs in PTSD to improve understanding of the neurocircuitry of PTSD. We conducted a literature search for PET and fMRI studies of PTSD that were published before February 2011. The article search resulted in 79 functional neuroimaging PTSD studies. Data from 26 PTSD peer-reviewed neuroimaging articles reporting results from 342 adult patients and 342 adult controls were included. Peak activation coordinates from selected articles were used to generate activation likelihood estimate maps separately for symptom provocation and cognitive-emotional studies of PTSD. A separate meta-analysis examined the coupling between ventromedial prefrontal cortex and amygdala activity in patients. Results demonstrated that the regions most consistently hyperactivated in PTSD patients included mid- and dorsal anterior cingulate cortex, and when ROI studies were included, bilateral amygdala. By contrast, widespread hypoactivity was observed in PTSD including the ventromedial prefrontal cortex and the inferior frontal gyrus. Furthermore, decreased ventromedial prefrontal cortex activity was associated with increased amygdala activity. These results provide evidence for a neurocircuitry model of PTSD that emphasizes alteration in neural networks important for salience detection and emotion regulation.
RES E AR C H Open Access
Quantitative meta-analysis of neural activity in
posttraumatic stress disorder
Jasmeet P Hayes
1,2,3*
, Scott M Hayes
2,3,4
and Amanda M Mikedis
1,2
Abstract
Background: In recent years, neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and
positron emission tomography (PET) have played a significant role in elucidating the neural underpinnings of
posttraumatic stress disorder (PTSD). However, a detailed understanding of the neural regions implicated in the
disorder remains incomplete because of considerable variability in findings across studies. The aim of this meta-
analysis was to identify consistent patterns of neural activity across neuroimaging study designs in PTSD to improve
understanding of the neurocircuitry of PTSD.
Methods: We conducted a literature search for PET and fMRI studies of PTSD that were published before February
2011. The article search resulted in 79 functional neuroimaging PTSD studies. Data from 26 PTSD peer-reviewed
neuroimaging articles reporting results from 342 adult patients and 342 adult controls were included. Peak
activation coordinates from selected articles were used to generate activation likelihood estimate maps separately
for symptom provocation and cognitive-emotional studies of PTSD. A separate meta-analysis examined the
coupling between ventromedial prefrontal cortex and amygdala activity in patients.
Results: Results demonstrated that the regions most consistently hyperactivated in PTS D patients included mid-
and dorsal anterior cingulate cortex, and when ROI studies were included, bilateral amygdala. By contrast,
widespread hypoactivity was observed in PTSD including the ventromedial prefrontal cortex and the inferior frontal
gyrus. Furthermore, decreased ventromedial prefrontal cortex activity was associated with increased amygdala
activity.
Conclusions: These results provide evidence for a neurocircuitry model of PTSD that emphasizes alteration in
neural networks important for salience detection and emotion regulation.
Keywords: Activation likelihood estimation, fMRI, PET, Amygdala, Anterior cingulate cortex, Ventromedial prefrontal
cortex, Salience network, Fear conditioning
Background
In the aftermath of highly distressing and shocking events
such as combat, genocide, and rape, a subset of individuals
develop posttraumatic stress disorder (PTSD), which is
characterized by distressing memories of the event,
physiological hyperarousal, and impairment in daily func-
tioning. With the growing interest in PTSD due in part to
its high prevalence among veterans of the Iraq and Af-
ghanistan wars, there is an urgency to understand the
neural pathogenesis of the disorder. Neuroimaging studies
have been conducted to examine brain regions involved in
PTSD [1-26]. Based on these findings and the non-human
animal literature, the prevailing neurocircuitry model of
PTSD suggests that PTSD can be understood in terms of
circuits involved in fear conditioning in the brain. Specific-
ally, this model suggests that heightened amygdala activity
gives privileged status to feared and threatening stimuli.
Whereas the ventromedial prefrontal cortex would nor-
mally temper amygdala activity, abnormal function of this
region reduces regulation of amygdala output [27]. Fur-
thermore, altered hippocampal function may result in
impaired ability to discern safe from dangerous contexts.
The aforementioned brain regions, which play a key
role in nonhuman animal fear conditioning [28], likely
* Correspondence: jphayes@bu.edu
1
National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA
2
Neuroimaging Research Center, VA Boston Healthcare System, Boston, MA,
USA
Full list of author information is available at the end of the article
Biology of
Mood & Anxiety Disorders
© 2012 Hayes et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9
http://www.biolmoodanxietydisord.com/content/2/1/9
play an important role in PTSD. PTSD is mor e likely to
develop following highly fear-provoking and life-
threatening events than less intense events [29]. Influen-
tial psychological theories of PTSD have empha sized the
role of fear structures and fear conditioning in the
development and maintenance of the disorder [30,31].
Furthermore, exposure therapy, which involves the prin-
ciples of extinction learning [30], is one of the most ef-
fective therapeutic interventions for PTSD.
However, fear con ditioning models are limited in their
ability to explain the full range of human experience and
emotion. Fear conditioning can occur outside of con-
scious awareness, yet conscious processes such as volun-
tary an d effortful avoidance of thoughts and memories
of the trau ma play a vital role in the developm ent and
maintenance of the disorder [32]. This has led to grow-
ing supposition that fear-circuitry models are unable to
fully accou nt for the heterogeneity of symptoms follow-
ing a traumatic event [33] and that anxiety and fear may
not be the central components in explaining PTSD
symptomatology as previously believed [34]. Accord-
ingly, the proposed revision of the Diagnostic and Statis-
tical Manual (DSM-V) may now recognize negative
cognitions and persistent negative mood states as key
symptoms of the diagnosis [35], suggesting that other
emotions such as dysphoria are important in the devel-
opment and maintenance of the disorder in addition to
fear. Therefore, a primary goal of the present study was
to examine patterns of brain activation in neuroimaging
studies of PTSD that may provide a more complete
understanding of the neural circuitry of PTSD.
In the present study, we performed a quantitative
meta-analysis of neuroimaging studies in PTSD using
activation likelihood estimation (ALE). This method cal-
culates the probability that a given voxel is activated
consistently across studies rather than a single study
[36] and therefore provides a more objective measure of
brain activity in PTSD than qualitative reviews. Al-
though there have been two prior functional neuroima-
ging meta-analyses in PTSD [37,38], the present study
includes more recent studies, focuses solely on adult
PTSD, and considers separately the effects of study type
(symptom provocation versus cognitive-emotional) and
neuroimaging analysis type (whole-brain voxel-wise ana-
lysis versus region-of-interest [ROI] analysis). Symptom
provocation studies are designed to elicit trauma-related
symptoms whereas cognitive-emotional studies include
emotional stimuli (e.g., fearful face) but do not explicitly
cue the patient to their traumatic event. In contrast to
previous meta-analyses in PTSD, the current stud y sepa-
rates symptom provocation and cognitive-emotional
studies to examine the neural correlates of two primary
characteristics of PTSD: specific recall of a traumatic
event (symptom provocation) and emotional response
generalization (cognitive-emotional studies). Further-
more, examining results from whole-brain vox el-wise
analyses separately from ROI analyses may provide
greater insight whether the regions typically targeted in
ROI studies (e.g., the amygdala) are also robustly active
when taking into account all voxels in the brain. ROI
analyses restrict statistical analysis to the small number
of a priori defined voxels, reducing the need for more
stringent correction for multiple comparisons; thus, ROI
studies are not entirely comparable to studies employing
whole-brain voxel-wise statistics. In the present study,
we examined the results from ROI studies as they com-
prise a significant proportion of imaging studies in
PTSD, with the recognition that whole brain voxel-wise
analyses represent a less biased statistical approach. Fi-
nally, we performed a separate meta-analysis to test the
fear-model hypothesis tha t hypoactivity in the ventro-
medial prefrontal cortex is associated with hyperactivity
in the amygdala, reflecting insufficient inhibition of pre-
frontal cortex over the amygdala.
Methods
Article selection
Using keyw ords PTSD,”“neuroimaging,”“fMRI, and
PET, a literature search in PubMed and Pub lished
International Literature on Traumatic Stress (PILOTS)
was conducted for PET and fMRI studies of adult PTSD
that were published before February 2011. The article
search resulted in 79 functional neuroimaging studies.
Included studies contrasted a traumatic or negative
emotional condition with a resting baseline, positive
condition, or neutral condition, conducted between-
group analyses using subtraction methodology, and
reported between-group peak activation coordinates in
standard space. For relevant articles that did not report
whole-brain results, the authors were contacted to re-
quest activation coordinates [6,10]. Case studies were
excluded [39,40] as well as studies examining PTSD and
co-morbidity with other disorders, although an excep-
tion was made for major depressive disorder (MDD) be-
cause of its high co-morbidity with PTSD [13]. Ba sed on
these inclusion and exclusion criteria, 26 adult PTSD
neuroimaging studies reporting results from 342 patients
and 342 controls remained in the analyses (see Table 1).
Inclusion/exclusion criteria for activation foci
For each of the articles listed in Table 1, significant peak
activation coordinates were extracted for negative > other
(baseline, positive, or neutral) between-group contrasts
(PTSD > Controls; Controls > PTSD). When coordinates
for more than one type of negative > other contrast were
reported in the same study, only one contrast was
included to avoid using foci from the same participants
twice [4,9,16,25]. In these cases, the selected contrast
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 2 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
Table 1 Functional neuroimaging studies included in meta-analysis
Study PTSD TC* NTC** Type of
trauma
Contrast used in
meta-analysis
Scanning task Imaging
method
Design
Symptom Provocation Whole Brain Analyses (10)
Bremner et al. 1999a 10 10 Combat Combat vs. neutral pictures
and sounds
View and listen PET Block
Bremner et al. 1999b 10 12 SA
+
Childhood abuse vs. neutral
scripts
Image and remember event PET Block
Britton et al. 2005 16 15 Combat Combat vs. neutral scripts Listen and maintain evoked
emotional state
PET Block
Hou et al. 2007 10 7 Mining
accident
Mining accident vs. neutral
pictures
View fMRI Block
Lanius et al. 2001 9 9 Mixed Trauma scripts vs. baseline Listen and remember event fMRI Block
Lanius et al. 2002 7 10 SA (1 MVA)
+
Trauma scripts vs. baseline Listen and remember event fMRI Block
Lanius et al. 2003 10 10 Mixed Trauma scripts vs. baseline Listen and remember event fMRI Block
Lanius et al. 2007 26 16 MVA
+
Trauma vs. neutral scripts Listen and remember event fMRI Block
Shin et al. 1999 8 8 SA
+
Sexual abuse vs. neutral scripts Recall and imagine contents
of script
PET Block
Shin et al. 2004 17 19 Combat Combat vs. neutral scripts Recall and imagine contents
of script
PET Block
Symptom Provocation ROI Analyses (2)
Frewen et al. 2008 25 16 MVA
+
Trauma vs. neutral scripts Listen to and image script fMRI Block
Protopopescu et al.
2005
9 14 SA, PA
+
PTSD vs. neutral words Read word fMRI Block
Cognitive-Emotional Whole Brain Analyses (12)
Bremner et al. 2003 10 11 SA
+
Negative emotional vs. neutral
word pairs
Declarative memory task PET Block
Bremner et al. 2004 12 9 SA
+
Negative emotional vs. neutral
words
Stroop task PET Block
Brunetti et al. 2010 10 10 Assault Negative emotional vs. neutral
IAPS pictures
Visuo-attentional task fMRI Block
Felmingham et al. 2010 23 21 Mixed Fearful vs. neutral faces Backward masking task fMRI Block
Fonzo et al. 2010 12 12 IPV
+
Fearful vs. happy faces Emotional face matching task fMRI Block
Kim et al. 2008 12 12 Fire Fearful vs. neutral faces Same-different judgment task fMRI Event-related
Sakamoto et al. 2005 16 16 Mixed Traumatic vs. neutral images View stimuli below perceptual
threshold
fMRI Block
Shin et al. 2005 13 13 Combat, fire Fearful vs. happy faces Overt passive viewing task fMRI Block
Thomaes et al. 2009 9 9 SA, PA
+
Negative words vs. baseline Word classification task fMRI Event-related
Whalley et al. 2009 16 16 16 Mixed Negative vs. neutral background
pictures with
neutral foreground pictures
Episodic memory retrieval
task
fMRI Event-related
Williams et al. 2006 13 13 Mixed Fearful vs. neutral faces Overt fear perception task fMRI Block
Hou et al. 2007 Same Hou et al. 2007 article as the one listed above (in addition to symptom provocation coordinates, article reported
coordinates from a short-term memory recall task)
Cognitive-Emotional ROI Analyses (6)
Bryant et al. 2008 15 15 Mixed Fearful vs. neutral faces View stimuli below conscious
threshold
fMRI Block
Phan et al. 2006 16 15 Combat Negative vs. neutral IAPS
pictures
View and rate pictures PET Block
Rauch et al. 2000 8 8 Combat Fearful vs. positive faces Masked faces paradigm fMRI Block
Felmingham et al.
2010
Same as whole brain article above
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 3 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
compared a trauma-specific or fear-inducing condition
with a neutral condition. If a study conducted a whole-
brain and a ROI analysis [8,9,12,26], coordinates from
both analyses were included provided that the ROIs
were not reported in the whole-brain results [8,9,26].
In studies that included two levels of control groups
(e.g., healthy controls and trauma-exposed controls) or
PTSD patients (e.g., PTSD with MDD versus PTSD
without MDD), only foci from one of the between-group
comparisons were used (i.e., between-group foci for
PTSD vs. traumatized controls [5,8] and P TSD without
co-morbidity vs. controls [13]). Following inclusion and
exclusion of coordinates, 218 between-group activation
foci remained (Table 2).
Meta-analyses
Coordinate-based random-effects meta-analyses were
conducted using GingerALE software version 2.1 (http://
brainmap.org/ale/). Coordinates reported in MNI space
were converted to Talairach space using the Lancaster
transform [41] as implemented in GingerALE. Coordi-
nates from symptom provocation and cognitive-
emotional tasks were first combined to examine the
neural regions involved across tasks and then were ana-
lyzed separately to examine differences between the two
design types. A replicate set of analyses was performed
that included ROI-based studies. Differences in the
whole-brain voxel-wise results with the inclusion of
ROIs, when present, are noted in the tables and results.
For each analysis reported, peak activation coordi-
nates were smoothed using a three-dimensional Gauss -
ian filter and transformed into Gaussian probability
distributions. These probability distributions were com-
bined to generate whole-brain statistical maps of the
ALE values o n a voxel-wise basis. ALE statistics calcu-
lated the probability that at lea st one of the foci lay
within each voxe l and, therefore, the likelihood that
each voxel wa s activated across all studies included in
the analysis. The ALE statistic maps were compar ed
with a null-distribution of random spatial a ssociat ions
between experiments (random-effe ct s model) to assess
for above chance clustering between experiments using
a threshold at false discovery rate (FDR) corre cted
P < 0.05 and a clus ter-extent of 100 mm
3
.
To explore the hypothesis that activity in the ventro-
medial prefrontal cortex and the amygdala was inversely
related, we first identified whole-brain studies that
reported increased ventromedial prefrontal cortex activ-
ity in controls relative to PTSD patient s (which would
suggestthatthisregionwashypoactiveinPTSD)and
also reported regions of increased activity in P TSD rela-
tive to controls. Six studies were identified that met
these criteria [1,11,12,21-23]. A meta-analysis wa s per-
formed on the coordinates from these studies for the
PTSD > Control contrast. Thus, we examined the
regions that were hyperactive in P TSD w hen the ventro-
medial prefrontal cortex was hypoactive. Due to the
small number of studies included, the analysis wa s thre-
sholded at FDR corre cted P <0.05 and a less conserva-
tive cluster-extent of 40 mm
3
(i.e., 5 contiguous voxels)
was u sed.
Results
Separate meta-analy ses were run to examine the neural
activity across and within symptom provocation and
cognitive-emotional tasks in PTSD. Because of the vari-
ability in naming conventions of medial prefrontal cor-
tex regions across different studies, activated regions are
listed in the text and tables both by their structure spe-
cific name (e.g., medial frontal gyrus) and a general
name signifying their contribution to a broader, less
defined area (e.g., ventromedial prefrontal cortex which
broadly includes the pregenual and subgenual anterior
cingulate cortex, medial orbitofrontal cortex, and the
ventral part of the medial prefrontal cortex).
Common activations for PTSD across tasks
The regions that were hyper- and hypoactive when stud-
ies were collapsed across task type (i.e., symptom provo-
cation and cognitive-emotional) in PTSD relative to
control subjects are reported in Table 3. We defined
hyperactivity in PTSD as the results stemming from the
PTSD > Control contrast and hypoactivity in PTSD as
brain regions active from the Control > PTSD contrast.
Patients with PTSD showed hyperactivation in the mid-
and dorsal anterior cingulate (Figure 1A), left superior
temporal gyrus , and left supplementary motor area.
Robust bilateral amygdala and left dorsomedial pre-
frontal cortex activity was observed when ROI studies
were included (Figure 1B).
Notably, there were several regions of hypoactivation
in PTSD relative to controls including the medial frontal
gyrus (ventromedial prefron tal cortex; Figure 1B), thal-
amus, right inferior frontal gyrus (Figure 1B), and right
Table 1 Functional neuroimaging studies included in meta-analysis (Continued)
Fonzo et al. 2010 Same as whole brain article above
Williams et al. 2006 Same as whole brain article above
*TC: trauma exposed controls without PTSD.
**NTC: non-traumatized controls.
+
SA: sexual abuse/assault; PA: physical abuse/assault; MVA : motor vehicle accident; NSA: non sexual assault; IPV: intimate partner violence.
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 4 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
middle temporal gyrus. When ROI studies were
included, the results remaine d consistent with additional
activity observed in the pregenual anterior cingulate cor-
tex (Table 3).
Symptom provocation studies
A meta-analysis of symptom provocation designs was
conducted to reveal the regions that were involved in re-
living ones traumatic event (Table 4). The regions con-
sistently hyperactivated in PTSD were the mid- and
dorsal anterior cingulate cortex. By contrast, widespread
hypoactivity was observed, including the medial frontal
gyrus (ventromedial prefrontal cortex), right inferior
frontal gyrus, and right precuneus. These results were
unchanged with the inclusion of ROI studies. Figure 2
displays brain activation separately for symptom provo-
cation and cognitive-emotional studies.
Cognitive-emotional studies
Cognitive-emotional studies included stimuli that were
negative, but not trauma-specific (e.g., fearful faces). The
whole-brain voxel-wise analysis revealed hyperactivity in
supplementary motor area. Bilateral amygdala and med-
ial frontal gyrus (dorsomedial prefrontal cortex, BA 8)
activity was observed when ROI studies were included
(see Table 4). Regions of hypoactivity (Figure 2) included
the pregenual anteri or cingulate cortex (ventromedial
prefrontal cortex) and medial frontal gyrus (dorsomedial
prefrontal cortex, BA 9).
Ventromedial prefrontal cortex meta-analysis
We next performed a meta-analysis on regions that were
hyperactive in PTSD within studies that reported
decreased ventromedial prefrontal cortex activity (see
Methods). The analysis showed that when the ventro-
medial prefrontal cortex was hypoactivated, greater
amygdala activation was observed in PTSD, supporting
the hypothesis that activity in the ventromedial pre-
frontal cortex and amygdala are inversely related. Other
regions that showed increased activity include d the right
middle and inferior temporal gyrus, left superior tem-
poral gyrus, bilateral precuneus, and right putamen
(Table 5).
Discussion
The present study used quantitative meta-analysis to
examine the pathophysiology of PTSD. The results con-
firmed involvement of a subset of regions implicated in
fear-circuitry models of PTSD, including robust hyper-
activity in the dorsal anterior cingulate cortex, hypoac-
tivity in the ventromedial prefrontal cortex in PTSD, and
an inverse relationship between activity in the ventro-
medial prefrontal cortex and amygdala. However, add-
itional regions were found to be hyper- and hypoactive
in PTSD, suggesting that a broader view of the neural
circuitry of PTSD should be considered. Collapsing
across symptom provocation and cognitive-emotional
studies, the whole-brain voxel-wise analysis revealed
hyperactivation of the mid/dorsal anterior cingulate
Table 2 Number of activation foci included in between-
group analyses
Study P > C
+
C>P
+
Statistical threshold
Symptom Provocation Whole Brain Analyses
Bremner et al. 1999a 5 5 P < .001
Bremner et al. 1999b 9 19 P < .001
Britton et al. 2005 1 P < .005
Hou et al. 2007 1 9 P < .005
Lanius et al. 2001 4 P < .001
Lanius et al. 2002 9 3 P < .001, > 10 voxels
Lanius et al. 2003 9 P < .001, > 10 voxels
Lanius et al. 2007 2 P < .05 cor., > 10 voxels
Shin et al. 1999 4 14 P < .001
Shin et al. 2004 1 3 P < .001
Symptom Provocation ROI Analyses
Protopopescu et al. 2005 1 P < .01 cor.
Frewen et al. 2008 3 P < .05, > 10 voxels
Cognitive-Emotional Whole Brain Analyses
Bremner et al. 2003 15 14 P < .01 cor.
Bremner et al. 2004 2 6 P < .005 cor., > 65 voxels
Brunetti et al. 2010 6 3 P < .001
Felmingham et al. 2010 1 P < .001, > 10 voxels
Fonzo et al. 2010 3 1 P < .05
Kim et al. 2007 7 6 P < .001
Sakamoto et al. 2005 1 4 P < .01
Shin et al. 2005 4 4 P < .001
Thomaes et al. 2009 2 P < .001
Whalley et al. 2009 3 1 P < .001
Williams et al. 2006 7 1 P < .001
Hou et al. 2007* 2 P < .005
Cognitive-Emotional ROI Analyses
Bryant et al. 2008 4 P < .05, > 3 voxels
Phan et al. 2006 1 P < .005 cor.
Rauch et al. 2000 1
P < .05
Felmingham et al. 2010** 9 P < .001, > 10 voxels
Fonzo et al. 2010** 2 P < .05
Williams et al. 2006** 2 4 P < .001
Total SP foci 30 72
Total cognitive-emotional foci 69 47
Total number of foci 99 119
+
P>C: PTSD patients > Controls; C>P: Controls > PTSD patients.
*Paper also reported symptom provocation coordinates.
**Papers also reported whole brain coordinates.
cor. = corrected for multiple comparisons.
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 5 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
Table 3 Between-group comparison of activity across symptom provocation and cognitive-emotional studies
Region Hemisphere Talairach BA Volume
(mm
3
)
xyz
PTSD > Controls
Whole Brain Analysis
Dorsal ACC R 17.3 38.35 15.53 32 672
Mid/Dorsal ACC R 3.49 3.51 34.37 24 400
Superior Temporal Gyrus L 63.02 47.37 18.13 22 152
Supplementary Motor Area L 22.02 1.55 57.56 6 112
Whole Brain + ROI Analysis
Amygdala R 22.86 1.06 13.32 1328
Amygdala L 25.95 0.02 17.87 1136
Dorsal ACC R 17.33 38.35 15.44 32 640
Mid/Dorsal ACC R 3.61 3.18 34.29 24 288
Medial Frontal Gyrus (dmPFC) R 1.08 31.44 37.87 8 216
Superior Temporal Gyrus L 63.15 47.34 18.13 22 144
Controls > PTSD
Whole Brain Analysis
Medial Frontal Gyrus (vmPFC) R 3.07 36.09 6.69 11 984
Thalamus L 4.12 14.12 17.89 480
Thalamus R 12.06 12.03 1.97 464
Inferior Frontal Gyrus R 16.02 21.76 12.36 47 440
Middle Occipital Gyrus L 31.42 86.95 1.35 18 392
Medial Frontal Gyrus R 6.23 48.66 9.06 10 344
Middle Temporal Gyrus R 45.03 68.88 13.16 39 336
Inferior Frontal Gyrus R 45.79 15.16 10.21 44 304
Precuneus R 24.34 56.37 38.59 7 280
Cerebellum R 35.16 82.16 20 272
Medial Frontal Gyrus R 11.89 42.19 24.43 9 272
Fusiform Gyrus L 51.87 47.57 15.78 37 256
Precuneus R 25.76 84.66 39.71 19 248
Superior Temporal Gyrus L 39.88 23.07 5.88 13 144
Cerebellum R 20 47.03 14.64 128
Inferior Frontal Gyrus R 41.45 39.85 7.14 46 112
Whole Brain + ROI Analysis
Pregenual ACC R 5.17 44.99 14.35 32 1824
Medial Frontal Gyrus (vmPFC) R 3.11 36.03 6.34 11 864
Thalamus L 4.12 14.11 17.88 480
Thalamus R 12.01 12.01 2 456
Inferior Frontal Gyrus R 16.14 21.75 12.28 47 424
Middle Occipital Gyrus L 31.35 86.97 1.34 18 384
Dorsal ACC L 6.43 9.14 25.01 24 368
Middle Temporal Gyrus R 44.97 68.82 13.1 39 328
Superior Frontal Gyrus L 23.94 50.88 8.8 10 256
Fusiform Gyrus L 51.75
47.62 15.77 37 248
Thalamus L 7.65 6.83 7.93 248
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 6 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
cortex, supplementary motor area, and superior tem-
poral gyrus in PTSD. These regions have been previously
shown to be part of a putative salience network that
processes autonomic, interoceptive, homeostatic, and
cognitive information of personal relevance [42,43]. Ul-
timately, the salience network helps an organism evalu-
ate whether stimuli in the environment should be
approached or avoided. Importantly, activity in this sali-
ence network is positively correlated with anxiety [43].
We propose that in PTSD, the behavioral man ifestation
of increased output of the salience network may provide
privileged cognitive resources to a broad range of salient
stimuli leading to hypervigilance and disruption of goal-
directed activity. This notion is consistent with observations
in PTSD patients of deficits in working memory for not
only trauma-related negative distractors, but also neutral
distractors [44], suggesting that a variety of stimuli become
potentially salient for patients with PTSD. From this view-
point, negative emotions other than fear can be associated
with the disorder, as long as they are salient and associated
with a stress response.
The dorsal anterior cingulate cortex is a key node in
the salience network. Earlier conceptualizations of the
region suggested that its role was primarily in cold
cognitive processes, in contrast to the ventral aspects of
the anterior cingulate cortex that were thought to be
involved in affective processing [45]. However, more re-
cent data have not corroborated a cognitive versus
A
L
m idACC
R
vmPFC
IFG
PTSD > CONTROLS
PTSD < CONTROLS
B
AMY
Figure 1 A. Brain regions associated with PTSD across symptom provocation and cognitive-emotional tasks in the whole-brain voxel-
wise analysis. B. Bilateral amygdala activity is observed after including symptom provocation and cognitive-emotional ROI studies to the
whole-brain voxel-wise results. Areas of hyperactivation in PTSD (PTSD > Control) are shown in yellow and areas of hypoactivation in PTSD
(Control > PTSD) are shown in blue. Amy = amygdala, IFG = inferior frontal gyrus, L = left, midACC = mid anterior cingulate cortex, R = right,
vmPFC = ventromedial prefrontal cortex.
Table 3 Between-group comparison of activity across symptom provocation and cognitive-emotional studies
(Continued)
Precuneus R 24.44 56.35 38.82 7 248
Inferior Frontal Gyrus R 45.69 14.86 10.31 44 240
Precuneus R 25.73 84.68 39.86 19 216
Cerebellum R 35.01 82 20 208
Superior Temporal Gyrus L 39.98 22.77 5.98 13 120
P < .05 FDR-corrected, cluster activation extent 100 mm
3
. ACC = anterior cingulate cortex, BA = Brodmann area, dmPFC = dorsomedial prefrontal cortex, L = left,
R = right, vmPFC = ventromedial prefrontal cortex.
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 7 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
Table 4 Between-group comparison results of symptom provocation articles and cognitive-emotional articles
Region Hemisphere Talairach BA Volume
(mm
3
)
xyz
SYMPTOM PROVOCATION
PTSD > Controls
Whole Brain Analysis
Dorsal ACC R 15.38 37.69 16.96 32 344
Mid/Dorsal ACC R 2.65 8.91 33.77 24 296
Mid/Dorsal ACC R 0.3 19.11 37.4 24 104
Whole Brain + ROI Analysis
Dorsal ACC R 15.38 37.69 16.96 32 344
Mid/Dorsal ACC R 2.65 8.91 33.77 24 296
Controls > PTSD
Whole Brain Analysis
Medial Frontal Gyrus (vmPFC) R 3.32 36.07 6.42 11 1152
Thalamus R 12 12 2 648
Thalamus L 4.02 14.02 17.98 648
Inferior Frontal Gyrus R 45.62 14.54 8.65 44 480
Precuneus R 25.83 84.66 39.57 19 296
Inferior Frontal Gyrus R 41.77 40.46 7.18 46 216
Medial Frontal Gyrus R 3.94 50.11 7.37 10 208
Whole Brain + ROI Analysis
Medial Frontal Gyrus (vmPFC) R 3.34 36.13 6.34 11 1168
Thalamus R 12 12 2 648
Thalamus L 4.03 14.01 17.97 648
Medial Frontal Gyrus R 0.63 47.89 5.66 10 504
Inferior Frontal Gyrus R 45.69 14.62 8.52 44 464
Precuneus R 25.83 84.66 39.57 19 296
Inferior Frontal Gyrus R 41.77 40.46 7.18 46 216
COGNITIVE- EMOTIONAL
PTSD > Controls
Whole Brain Analysis
Supplementary Motor Area L 22.13 1.49 57.27 6 128
Supplementary Motor Area L 25.39 2.02 40.31 6 104
Whole Brain + ROI Analysis
Amygdala R 22.93 1.03 13.28 1376
Amygdala L 27.21 0.16 17.37 840
Medial Frontal Gyrus (dmPFC) R 0.98 31.46 37.87 8 224
Controls > PTSD
Whole Brain Analysis
Pregenual ACC (vmPFC) L 13.93 49.87 2.12 32 400
Medial Frontal Gyrus (dmPFC) R 10.63 40.6 23.03 9 272
Whole Brain + ROI Analysis
Medial Frontal Gyrus (dmPFC) R 11.17 41.96 21.25 9 984
Pregenual ACC (vmPFC) L 13.97 49.76 2.16 32 384
P < 0.05 FDR-corrected, activation extent 100 mm
3
. ACC = anterior cingulate cortex, BA = Brodman area, dmPFC = dorsomedial prefrontal cortex, L = left, R = right,
vmPFC = ventromedial prefrontal cortex.
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 8 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
affective dissociation. Recent reviews have called atten-
tion to the involvement of the dorsal anterior cingulate
cortex in PTSD [46,47], whic h may subserve learned
fear, fear appraisal and expression , and sympathetic ac-
tivity [48]. More broadly, dorsomedial prefrontal regions
(including the dorsal anterior cingulate cortex) have
been associ ated with appraisal and evaluation whereas
ventromedial prefrontal regions are associated with
regulatory functions. This dissociation is consistent with
the findings reported here, where more dorsal prefrontal
regions, including the dorsomedial prefrontal cortex and
mid/dorsal anterior cingulate cortex were active in
patients with PTSD and may suggest heightened apprai-
sals of potential threats in the envir onment, whereas
hypoactivity in ventromedial prefrontal regions may re-
flect dysfunction in emotion regulation.
Interestingly, the present results highlight the con tri-
bution of the mid-cingulate in PTSD, adding to the
growing evidence that this region plays an important
role in this disorder [49-51] and may be important for
fear conditioning [52]. The dorsa l anterior cingulate
spans a large area, encompassing BAs 24, 32, and 33.
Whereas a more anterior portion of the dorsal anterior
cingulate was activated in both PTSD patients and con-
trol subjects in the present meta-analysis, a more poster-
ior region was hyperactivated only in PTSD. A pre vious
study demonstrated that individuals with severe PTSD
symptomatology activated the mid/dorsal anterior cingu-
late to a greater extent than controls during an emo-
tional oddball task, suggesting that distracting stimuli
are given attentional preference at the expense of a goal-
relevant task in P TSD [49]. These findings provide con-
verging evidence for the role of the mid/dorsal anterior
cingulate cortex in salience processing. Another region
in the salience network, the amygdala, was observed
only when using a less stringent spatial extent in the
whole-brain analysis or when considering ROI analyses.
The amygdala is notoriously difficult to image due to
L
S
midACC
dmPFC
L
MA
IFG
vmPFC
Thal
vmPFC
L
PTSD > CONTROLS: Sym Prov
PTSD < CONTROLS: Sym Prov
> CONTROLS: Cog-
PTSD < CONTROLS: Cog-Emo
PTSD CONTROLS: Emo
Figure 2 Overlay of brain regions associated with PTSD by task design. Warm colors indicate regions of hyperactivity in PTSD patients
during symptom provocation study designs (red) and cognitive-emotional study designs (yellow). Cool colors indicate regions of hypoactivity in
PTSD during symptom provocation designs (purple) and cognitive-emotional designs (blue). Cog-Emo = Cognitive-emotional,
DmPFC = dorsomedial prefrontal cortex, IFG = inferior frontal gyrus, L = left, midACC = mid anterior cingulate cortex, SMA = supplementary motor
area, Sym Prov = symptom provocation, Thal = thalamus, vmPFC = ventromedial prefrontal cortex.
Table 5 Ventromedial prefrontal cortex meta-analysis results
Region Hemisphere Talairach BA Volume (mm
3
)
xyz
PTSD > Controls
Middle Temporal Gyrus R 49.54 36.22 12.82 20 136
Amygdala L 19.01 0.97 19.03 64
Precuneus L 12.98 53.03 33.02 31 64
Putamen R 19.43 1.15 7.72 56
Cerebellum R 36.64 65.35 37.02 48
Amygdala R 19.35 0.65 18.99 48
Superior Temporal Gyrus L 62.66 48.01 18.66 22 48
Precuneus R 20.65 76.99 40.66 7 48
Supplementary Motor Area L 47.98 4.01 41.66 6 48
Inferior Temporal Gyrus R 54.78 45.22 11.61 20 40
P < .05 FDR-corrected, activation extent 40 mm
3
. BA = Brodmann area, L = left, R = right.
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 9 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
vulnerability to susceptibility artifact and its relatively
small volume, which could accou nt for lack of robust
findings in the whole-brain analysis. Alternatively, it is
possible that the amygdala is not as central of a region
in PTSD as current neurocircuitry models suggest,
consistent with pre vious meta-analysis data showing that
the amygdala is more frequently active in patients
with social anxiety disorder and specific phobia than
PTSD [37].
With the addition of ROI analyses, amygdala activity
was observed for cognitive-emotional tasks but not
symptom provocation tasks, suggesting that the type of
task employed within a study influences amygdala activ-
ity in PTSD. There is emerging recognition that the
amygdala may play a more general role in processing
ambiguous and salient stimuli in the environment
[53-55], of which fear may be one particularly potent in-
stance. The amygdala, which is composed of several dis-
tinct but highly interconnected nuclei, is not specific to
fear states but is also activated for unusual and novel
stimuli [56] and unpredictability [57]. Therefore, the
stimuli and study designs employed during cognitive-
emotional studies of PTSD, which often present novel
and ambiguous stimuli intermittently, may evoke more
central involvement of the amy gdala than autobiograph-
ical trauma script s, which were often familiar and unam-
biguous from the start. Other explanations for the lack
of amygdala activity in symptom provocation designs are
less likely. Both the symptom provocation designs and
the cognitive-emotional ROI studies (in which amy gdala
activity was observed most robustly) were block designs;
therefore, the results are unlikely to be attributable to
differences in neuroimaging experimental design (i.e.,
event-related vs. block designs). Furthermore, the major-
ity of both symptom provocation and cognitive-
emotional studies were fMRI rather than PET, suggest-
ing that the difference is not due to imaging modality.
The discrepancy in amygdala activity for cognitive-
emotional and symptom provocation studies under-
scores the importance of considering the cognitive task
when interpreting activation differences (or lack thereof)
in the amygdala in PTSD and control participants.
In the present stud y, widespread hypoactivity in pre-
frontal cortex in PTSD was observed, including both
medial and lateral regions. Notably, hypoactivity in the
ventromedial prefrontal cortex was present in both
symptom provocation and cognitive-emotional study
designs. To examine the relationship between the
ventromedial prefrontal cortex and amygdala, we per-
formed a meta-analysis that identified regions of hyper-
activity within a subset of studies that showed a decrease
in ventromedial prefrontal cortex activity in PTSD
patients. We reasoned that under conditions of dimin-
ished ventrom edial prefrontal cortex activity, which may
signify reduced top-down governance of interconnected
regions, we would observe greater amygdala activity.
The results showed that when the ventromedial pre-
frontal cortex was hypoactive, the amygdala, putamen,
and temporal cortex were hyperactivated. These results
support the notion that a consequence of hypoactivity of
the ventromedial prefrontal cortex may be greater
responsivity of the amygdala in the face of negative in-
formation. Although the direction of this effect cannot
be determined conclusively because the neural connec-
tions between the amygdala and ventromedial prefrontal
cortex are bidirection al, there is a well-established litera-
ture showing the involvement of ventromedial prefrontal
cortex in regulatory control across species [58]. It is im-
portant to note that the ventromedial prefrontal cortex
is not a single entity, but rather is composed of multiple
distinct regions (i.e., subgenual and pregenual anterior
cingulate cortex, medial portions of orbitofrontal gyrus,
and medial frontal gyrus) that subserve a variety of func-
tions. For instance, the non-human animal literature
suggests that bordering divisions within ventromedial
prefrontal cortex may be responsible for both inhibition
and facilitation of autonomic arousal [58]. This may help
to explain why some studies of PTSD show increased ac-
tivation in this region [59] and suggests that a more
fine-grained analysis is required to better elucidate the
various functions of the ventromedial prefrontal cortex.
Nevertheless, the results of the current meta-analysis
show robust hypoactivation in the ventromedial pre-
frontal cortex consistent across task type, underscoring
its hypothesized role in regulatory control.
Importantly, additional prefrontal cortex regions such
as the inferior frontal gyrus were hyp oactivated in PTSD.
This finding is notable as previous work ha s implicated
the role of inferior frontal gyrus in emotion regu lation,
including inhibition from emotional distraction [60] and
emotional thought suppression [61]. Moreover, the infer-
ior frontal gyrus is purported to be involved in a net-
work of lateral prefrontal cortex regions involved in
changing ones negative thoughts to reduce the impact
of negative feelings (i.e., cognitive reappraisal) [62]. Al-
though speculative, it is possible that decreased activity
in lateral prefrontal cortex may reflect PTSD patients
difficulty challenging negative thoughts to cope with
emotional stimuli. Contemporary psychological models
of P TSD highlight the role of negative appraisals and
emotion regulation in the etiology and maintenance of
PTSD. One of the most successful psychosocial inter-
ventions for PTSD, cognitive processing therapy, is
based upon the notion that faulty cognitions and inter-
pretation surrounding the traumat ic event interferes
with the natural recovery pro cess after a trauma [63].
For example, a female rape victim who misattributes
blame to herself for attending a party where the rape
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 10 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
occurred may then mistrust her decisions in every aspect
of her life, leading to experiential avoidance and with-
drawal from social relationships. Research has supported
the notion that negative self-appraisals are associated
with PTSD symptom maintenance [64] and therefore
the DSM-V may now include the presence of negative
cognitions as a core feature of the disorder [35]. Cogni-
tive processing therapy encourages the patient to adopt
a more balanced view of the circumstances surrounding
the traumatic event, as well as current personal events
by challenging negative thoughts. Given the present
results, future studies should examine whether indivi-
duals who benefitted from cognitive processing therapy
recruit the inferior frontal gyrus to a greater extent com-
pared to pre-therapy, as well as compared to individuals
who did not benefit from therapy.
Limitations
A constraint of the current study is the availability of
studies that met our criteria for inclusion into the ana-
lyses. Although the literature search started with 79
studies, the exclusion of studies that did not include
stereotaxic coordinates likely reduced our power to de-
tect less robust activations. Although the number of foci
included in this study is more than the minimum
recommended for a meta-analysis, it remains an open
question whether a larger sample will reveal additional
networks central to the PTSD diagnosis. For example,
amygdala activity was observed in the PTSD group only
when considering ROI analyses or using a less stringent
spatial extent. Therefore, the limited number of studies
available for the meta-analysis may have had an impact
on the ability to detect amygdala activity within the
whole-brain analysis. Activity in another key node within
the salience network, the anterior insula, wa s observed
in the PTSD group using a less stringent cluster thresh-
old (FDR corrected, P < 0.05, cluster-extent = 24 mm
3
).
Future studies could isolate resting-state networks as a
more powerful and robust method towards understanding
the functional connections between nodes of the salience
network in PTSD. Interestingly, a recent resting-state
study in PTSD revealed greater connectivity between the
amygdala and insula in patients with PTSD than trauma-
exposed controls [65]. The results are consistent with the
notion that key nodes within the salience network are
highly coactive in PTSD and may underlie the hallmark
symptoms of the disorder.
Although there is convinc ing evidence that the hippo-
campus becomes dysfunctional as a result of chronic
stress [66] and activity in this region has shown to be
negatively correlated with arousal symptoms in PTSD
[67], hippocampal activity was not observed in the
present meta-analysis making it unclear how this region
contributes to neurocircuitry models of PTSD. Many of
the tasks included in this meta-analysis were not optimal
for eliciting hippocampal activity and those that do
examine hippocampal function in PTSD show mixed
results. There is a growing functional neuroimaging lit-
erature examining learning and memory in P TSD, which
may clarify the role of hippocampus given that these
types of paradigms traditionally activate the hippocam-
pus in healthy individuals.
Finally, working with a limited sample required inclu-
sion of studies with patients on medication and/or co-
morbid depression. As additional studies are published
and software development continues, future meta-
analyses may be able to focus exclusively on PTSD or in-
clude depression and medication status as covariates in
the analyses.
Conclusions
The goal of the present meta-analysis was to examine
the neurocircuitry of PTSD by considering a set of stud-
ies that were diverse in terms of functional imaging mo-
dality, study design, and PTSD trauma type. The results
provide evidence for hyperactivation of regions import-
ant for vigilance and salience detection, and hypoactiva-
tion of regulatory networks engaged in regulation of
autonomic arousal and cognition. The key salience net-
work regions that appear to be important in PTSD in-
clude the dorsomedial prefrontal cortex (including mid/
dorsal anterior cingulate cortex), supplementary mot or
area, and superior temporal gyrus.
Furthermore, regulatory control regions include two
primary networks that appear to be dysfunctional in
PTSD, including ventromedial prefrontal cortex control
over the amygdala and lateral prefrontal regions puta-
tively involved in modification of thought and inhibition
of distracting emotions. This model is consistent with
the findings that therapies designed to both extinguish
fear responses and promote emotion regulation through
challenging negative cognitions are helpful for the treat-
ment of P TSD.
Competing interests
The author(s) declare that they have no competing interests.
Authors contributions
Ms. Amanda Mikedis conducted a literature review, performed data analysis,
and assisted in writing the Methods section. Dr. Jasmeet Hayes and Dr. Scott
Hayes helped with the literature review and data analysis, and wrote the
paper. All authors read and approved the final manuscript.
Acknowledgements
We would like to thank Drs. Marcella Brunetti and Ruth Lanius for providing
unpublished activation coordinates for inclusion in the current meta-analysis,
and Dr. Lisa Shin for providing insightful comments on the manuscript. This
work was supported by the National Institutes of Health, National Institutes
of Mental Health [grant number K23 MH084013 awarded to JPH] and the
Department of Veterans Affairs, Veterans Health Administration,
Rehabilitation Research & Development Service [grant number CDA E7822W
awarded to SMH]. These funding sources had no further role in the study
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 11 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
analysis, interpretation of the data, writing of the report, or approval of the
paper.
Author details
1
National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.
2
Neuroimaging Research Center, VA Boston Healthcare System, Boston, MA,
USA.
3
Department of Psychiatry, Boston University School of Medicine,
Boston, MA, USA.
4
Memory Disorders Research Center, VA Boston Healthcare
System and Boston University School of Medicine, Boston, MA, USA.
Received: 16 February 2012 Accepted: 26 April 2012
Published: 18 May 2012
References
1. Bremner JD, Narayan M, Staib LH, Southwick SM, McGlashan T, Charney DS:
Neural correlates of memories of childhood sexual abuse in women with
and without posttraumatic stress disorder. Am J Psychiatry 1999,
156:17871795.
2. Bremner JD, Staib LH, Kaloupek D, Southwick SM, Soufer R, Charney DS: Neural
correlates of exposure to traumatic pictures and sound in Vietnam combat
veterans with and without posttraumatic stress disorder: A positron
emission tomography study. Biol Psychiatry 1999, 45:806816.
3. Bremner JD, Vermetten E, Vythilingam M, Afzal N, Schmahl C, Elzinga B, et
al: Neural correlates of the classic color and emotional Stroop in women
with abuse-related posttraumatic stress disorder. Biol Psychiatry 2004,
55:612620.
4. Bremner JD, Vythilingam M, Vermetten E, Southwick SM, McGlashan T, Staib
LH, et al: Neural correlates of declarative memory for emotionally
valenced words in women with posttraumatic stress disorder related to
early childhood sexual abuse. Biol Psychiatry 2003, 53:879889.
5. Britton JC, Phan KL, Taylor SF, Fig LM, Liberzon I: Corticolimbic blood flow
in posttraumatic stress disorder during script-driven imagery. Biol
Psychiatry 2005, 57:832840.
6. Brunetti M, Sepede G, Mingoia G, Catani C, Ferretti A, Merla A, et al:
Elevated response of human amygdala to neutral stimuli in mild post
traumatic stress disorder: Neural correlates of generalized emotional
response. Neuroscience 2010, 168:670 679.
7. Bryant RA, Kemp AH, Felmingham KL, Liddell B, Olivieri G, Peduto A, et al:
Enhanced amygdala and medial prefrontal activation during
nonconscious processing of fear in posttraumatic stress disorder: An
fMRI study. Hum Brain Mapp 2008, 29:517523.
8. Felmingham K, Williams LM, Kemp AH, Liddell B, Falconer E, Peduto A, et al:
Neural responses to masked fear faces: Sex differences and trauma
exposure in posttraumatic stress disorder. J Abnorm Psychol 2010,
119:241247.
9. Fonzo GA, Simmons AN, Thorp SR, Norman SB, Paulus MP, Stein MB:
Exaggerated and disconnected insular-amygdalar blood oxygenation
level-dependent response to threat-related emotional faces in women
with intimate-partner violence posttraumatic stress disorder. Biol
Psychiatry 2010, 68:433441.
10. Frewen P, Lane RD, Neufeld RWJ, Densmore M, Stevens T, Lanius R: Neural
correlates of levels of emotional awareness during trauma script-
imagery in posttraumatic stress disorder.
Psychosom Med 2008, 70:2731.
11. Hou C, Liu J, Wang K, Li L, Liang M, He Z, et al: Brain responses to
symptom provocation and trauma-related short-term memory recall in
coal mining accident survivors with acute severe PTSD. Brain Res 2007,
1144:165174.
12. Kim MJ, Chey J, Chung A, Bae S, Khang H, Ham B, et al: Diminished rostral
anterior cingulate activity in response to threat-related events in
posttraumatic stress disorder. J Psychiatr Res 2008, 42:268277.
13. Lanius RA, Frewen PA, Girotti M, Neufeld RW, Stevens TK, Densmore M:
Neural correlates of trauma script-imagery in posttraumatic stress
disorder with and without comorbid major depression: A functional MRI
investigation. Psychiat Res-Neuroim 2007, 155:4556.
14. Lanius RA, Williamson PC, Boksman K, Densmore M, Gupta M, Neufeld RW,
et al : Brain activation during script-driven imagery induced dissociative
responses in PTSD: A functional magnetic resonance imaging
investigation. Biol Psychiatry 2002, 52:305311.
15. Lanius RA, Williamson PC, Densmore M, Boksman K, Gupta MA, Neufeld RW, et
al: Neural correlates of traumatic memories in posttraumatic stress disorder:
A functional MRI investigation. Am J Psychiatry 2001, 158:19201922.
16. Lanius RA, Williamson PC, Hopper J, Densmore M, Boksman K, Gupta MA, et
al: Recall of emotional states in posttraumatic stress disorder: An fMRI
investigation. Biol Psychiatry 2003, 53:204210.
17. Phan KL, Britton JC, Taylor SF, Fig LM, Liberzon I: Corticolimbic blood flow
during nontraumatic emotional processing in posttraumatic stress
disorder. Arch Gen Psychiatry 2006, 63:184192.
18. Protopopescu X, Pan H, Tuescher O, Cloitre M, Goldstein M, Engelien W, et
al: Differential time courses and specificity of amygdala activity in
posttraumatic stress disorder subjects and normal control subjects. Biol
Psychiatry 2005, 57:464473.
19. Rauch SL, Whalen PJ, Shin LM, McInerney SC, Macklin ML, Lasko NB, et al:
Exaggerated amygdala response to masked facial stimuli in
posttraumatic stress disorder: A functional MRI study. Biol Psychiatry 2000,
47:
769776.
20. Sakamoto H, Fukuda R, Okuaki T, Rogers M, Kasai K, Machida T, et al:
Parahippocampal activation evoked by masked traumatic images in
posttraumatic stress disorder: A functional MRI study. Neuroimage 2005,
26:813821.
21. Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, Alpert NM, et al:
Regional cerebral blood flow during script-driven imagery in childhood
sexual abuse-related PTSD: A PET investigation. Am J Psychiatry 1999,
156:575584.
22. Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, Lasko NB, et al: Regional
cerebral blood flow in the amygdala and medial prefrontal cortex
during traumatic imagery in male and female Vietnam veterans with
PTSD. Arch Gen Psychiatry 2004, 61:168176.
23. Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Martis B, et al: A
functional magnetic resonance imaging study of amygdala and medial
prefrontal cortex responses to overtly presented fearful faces in
posttraumatic stress disorder. Arch Gen Psychiatry 2005, 62:273281.
24. Thomaes K, Dorrepaal E, Draijer N, de Ruiter M, Elzinga B, van Balkom A, et
al: Increased activation of the left hippocampus region in Complex PTSD
during encoding and recognition of emotional words: A pilot study.
Psychiat Res-Neuroim 2009, 171:4453.
25. Whalley MG, Rugg MD, Smith APR, Dolan RJ, Brewin CR: Incidental retrieval
of emotional contexts in post-traumatic stress disorder and depression:
An fMRI study. Brain Cognition 2009, 69:98107.
26. Williams LM, Kemp AH, Felmingham K, Barton M, Olivieri G, Peduto A, et al:
Trauma modulates amygdala and medial prefrontal responses to
consciously attended fear. Neuroimage 2006, 29:347357.
27. Rauch SL, Shin LM, Phelps EA: Neurocircuitry models of posttraumatic
stress disorder and extinction: Human neuroimaging research - Past,
present, and future. Biol Psychiatry 2006, 60:376382.
28. LeDoux JE: Emotion circuits in the brain. Annu Rev Neurosci 2000, 23:155184.
29. Kilpatrick DG, Resnick HS, Acierno R: Should PTSD Criterion A be retained?.
J Trauma Stress 2009, 22:374
383.
30. Foa EB, Kozak MJ: Emotional processing of fear: Exposure to corrective
information. Psychol Bull 1986, 99:2035.
31. Keane T, Fairbank J, Caddell J, Zimering R, Bender M: A behavioral
approach to assessing and treating post-traumatic stress disorder in
Vietnam Veterans.InTrauma and its Wake: The Study and Treatment of
Post-traumatic Stress Disorder. Edited by Bristol FC. PA: Brunner/Mazel;
1985:257294.
32. Ehlers A, Mayou RA, Bryant B: Psychological predictors of chronic
posttraumatic stress disorder after motor vehicle accidents. J Abnorm
Psychol 1998, 107:508519.
33. Suvak MK, Barrett LF: Considering PTSD from the perspective of brain
processes: A psychological construction approach. J Trauma Stress 2011,
24:324.
34. Resick PA, Miller MW: Posttraumatic stress disorder: Anxiety or traumatic
stress disorder?. J Trauma Stress 2009, 22:384390.
35. Friedman MJ, Resick PA, Bryant RA, Brewin CR: Considering PTSD for DSM
5. Depress Anxiety 2011, 28:750769.
36. Turkeltaub PE, Eden GF, Jones KM, Zeffiro TA: Meta-analysis of the
functional neuroanatomy of single-word reading: Method and
validation. Neuroimage 2002, 16:765780.
37. Etkin A, Wager TD: Functional neuroimaging of anxiety: A meta-analysis
of emotional processing in PTSD, social anxiety disorder, and specific
phobia. Am J Psychiatry 2007, 164:14761488.
38. Simmons AN, Matthews SC: Neural circuitry of PTSD with or without mild
traumatic brain injury: A meta-ana lysis. Neuropharmacology 2012, 62:598606.
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 12 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
39. Flatten G, Perlitz V, Pestinger M, Arin T, Kohl B, Kastrau F, et al: Neural
processing of traumatic events in subjects suffering PTSD-a case study
of two surgical patients with severe accident trauma. GMS Psycho-social
Medicine 2004, 1:110.
40. Lanius RA, Hopper JW, Menon RS: Individual differences in a husband and
wife who developed PTSD after a motor vehicle accident: A functional
MRI case study. Am J Psychiatry 2003, 160:667669.
41. Laird AR, Robinson JL, McMillan KM, Tordesillas-Gutierrez D, Moran ST,
Gonzales SM, et al : Comparison of the disparity between Talairach and
MNI coordinates in functional neuroimaging data: Validation of the
Lancaster transform. Neuroimage 2010, 51:677683.
42. Downar J, Crawley AP, Mikulis DJ, Davis KD: A cortical network sensitive to
stimulus salience in a neutral behavioral context across multiple sensory
modalities. J Neurophysiol 2002, 87:615620.
43. Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, et al:
Dissociable intrinsic connectivity networks for salience processing and
executive control. J Neurosci 2007, 27:23492356.
44. Morey R, Dolcos F, Petty C, Cooper D, Hayes J, LaBar K, et al: The role of
trauma-related distractors on neural systems for working memory and
emotion processing in posttraumatic stress disorder. J Psychiatr Res 2009,
43:809817.
45. Bush G, Luu P, Posner MI: Cognitive and emotional influences in anterior
cingulate cortex. Trends Cogn Sci 2000, 4:215222.
46. Hughes KC, Shin LM: Functional neuroimaging studies of post-traumatic
stress disorder. Expert Rev Neurother 2011, 11:275285.
47. Shin LM, Handwerger K: Is posttraumatic stress disorder a stress-induced
fear circuitry disorder?. J Trauma Stress 2009, 22:409415.
48. Etkin A, Egner T, Kalisch R: Emotional processing in anterior cingulate and
medial prefrontal cortex. Trends Cogn Sci 2011, 15:85
93.
49. Pannu Hayes J, LaBar K, Petty C, McCarthy G, Morey R: Alterations in the
neural circuitry for emotion and attention associated with posttraumatic
stress symptomatology. Psychiat Res-Neuroim 2009, 172:715.
50. Shin LM, Bush G, Milad MR, Lasko NB, Brohawn KH, Hughes KC, et al:
Exaggerated activation of dorsal anterior cingulate cortex during
cognitive interference: A monozygotic twin study of posttraumatic stress
disorder. Am J Psychiatry 2011, 168:979985.
51. Shin LM, Lasko NB, Macklin ML, Karpf RD, Milad MR, Orr SP, et al: Resting
metabolic activity in the cingulate cortex and vulnerability to
posttraumatic stress disorder. Arch Gen Psychiatry 2009, 66:10991107.
52. Milad MR, Quirk GJ, Pitman RK, Orr SP, Fischl B, Rauch SL: A role for the
human dorsal anterior cingulate cortex in fear expression. Biol Psychiatry
2007, 62:1191 1194.
53. Davis M, Whalen PJ: The amygdala: Vigilance and emotion. Mol Psychiatr
2001, 6:1334.
54. Pessoa L, Adolphs R: Emotion processing and the amygdala: From a 'low
road' to 'many roads' of evaluating biological significance. Nat Rev
Neurosci 2010, 11:773 783.
55. Whalen PJ: Fear, vigilance, and ambiguity: Initial neuroimaging studies of
the human amygdala. Curr Dir Psychol Sci 1998, 7:177188.
56. Blackford JU, Buckholtz JW, Avery SN, Zald DH: A unique role for the
human amygdala in novelty detection. Neuroimage 2010, 50:11881193.
57. Sarinopoulos I, Grupe D, Mackiewicz K, Herrington J, Lor M, Steege E, et al:
Uncertainty during anticipation modulates neural responses to aversion
in human insula and amygdala. Cereb Cortex 2010, 20:929940.
58. Quirk GJ, Beer JS: Prefrontal involvement in the regulation of emotion:
convergence of rat and human studies. Curr Opin Neurobiol 2006, 16:723727.
59. Morey RA, Petty CM, Cooper DA, LaBar KS, McCarthy G: Neural systems for
executive and emotional processing are modulated by symptoms of
posttraumatic stress disorder in Iraq War veterans. Psychiat Res-Neuroim
2008, 162:5972.
60. Dolcos F, McCarthy G: Brain systems mediating cognitive interference by
emotional distraction. J Neurosci 2006, 26:20722079.
61. Depue B, Curran T, Banich M: Prefrontal regions orchestrate suppression of
emotional memories via a two-phase process. Science 2007, 317:215219.
62. Ochsner KN: Forbetterorforworse:Neuralsystems supporting the cognitive
down- and up-regulation of emotion. Neuroimage 2004, 23:483499.
63. Resick PA, Monson C, Chard K: Cognitive processing therapy: Veteran/military
version. Washington DC: Department of Veterans' Affairs; 2008.
64. Owens G, Cox TA, Chard K: The relationship between maladaptive
cognitions, anger expression, and posttraumatic stress disorder among
Veterans in residential treatment. Journal of Aggression, Maltreatment &
Trauma 2008, 17:439452.
65. Rabinak CA, Angstadt M, Welsh RC, Kennedy A, Lyubkin M, Martis B, et al:
Altered amygdala resting-state functional connectivity in post-traumatic
stress disorder. Front. Psychiatry 2011, 2:62.
66. Ulrich-Lai YM, Herman JP: Neural regulation of endocrine and autonomic
stress responses. Nat Rev Neurosci 2009, 10:397409.
67. Hayes J, LaBar K, McCarthy G, Selgrade E, Nasser J, Dolcos F, et al: Reduced
hippocampal and amygdala activity predicts memory distortions for
trauma reminders in combat-related PTSD. J Psychiatr Res 2011, 45:660669.
doi:10.1186/2045-5380-2-9
Cite this article as: Hayes et al.: Quantitative meta-analysis of neural
activity in posttraumatic stress disorder. Biology of Mood & Anxiety
Disorders 2012 2 :9.
Submit your next manuscript to BioMed Central
and take full advantage of:
Convenient online submission
Thorough peer review
No space constraints or color figure charges
Immediate publication on acceptance
Inclusion in PubMed, CAS, Scopus and Google Scholar
Research which is freely available for redistribution
Submit your manuscript at
www.biomedcentral.com/submit
Hayes et al. Biology of Mood & Anxiety Disorders 2012, 2:9 Page 13 of 13
http://www.biolmoodanxietydisord.com/content/2/1/9
    • "Inconsistencies in the brain–behavior relationship associated with the 9/11 condition in passengers and the comparison group may also be due to greater error variance attributable to individual differences in media exposure. As noted in the introduction, studies of traumatic memory have inconsistently reported amygdalar activation , but these studies largely focus on PTSD effects (Driessen et al., 2004; Fischer et al., 1996; Hayes et al., 2012; Lanius et al., 2001; Patel et al., 2012). In the present study, we were unable to explore hypotheses related to PTSD status versus trauma exposure per se, given the restricted range of PTSD symptomatology across subjects and the lack of individuals with an active diagnosis. "
    [Show abstract] [Hide abstract] ABSTRACT: We investigated the neural correlates of remote traumatic reexperiencing in survivors of a life-threatening incident: the near crash of Air Transat (AT) Flight 236. Survivors’ brain activity was monitored during video-cued recollection of the AT disaster, September 11, 2001 (9/11), and a comparatively nonemotional (neutral) event. Passengers showed a robust memory enhancement effect for the AT incident relative to the 9/11 and neutral events. This traumatic memory enhancement was associated with activation in the amygdala, medial temporal lobe, anterior and posterior midline, and visual cortex in passengers. This brain–behavior relationship also held in relation to 9/11, which had elevated significance for passengers given its temporal proximity to the AT disaster. This pattern was not observed in a comparison group of nontraumatized individuals who were also scanned. These findings suggest that remote traumatic memory is mediated by amygdalar activity, which likely enhances vividness via influence
    Article · Jun 2015
    • "About 30% of individuals who experience traumatic life events develop posttraumatic stress disorder (PTSD; Nemeroff et al., 2006), which is characterized by a general impairment in the ability to extinguish fear responses (Jovanovic et al., 2010; Norrholm et al., 2011). Patients suffering from PTSD exhibit reduced ventromedial prefrontal cortex (vmPFC) activation and heightened amygdala activation (Hayes et al., 2012; Stevens et al., 2013). Similarly, experiments in rat models of fear learning suggest that the vmPFC is required for the modulation and expression of extinction memory (Sierra- Mercado et al., 2011) and that plasticity in the vmPFC-amygdala pathway underlies the suppression of fear via attenuation of central amygdala activity (Marek et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Fearful experiences can produce long-lasting and debilitating memories. Extinction of the fear response requires consolidation of new memories that compete with fearful associations. Subjects with posttraumatic stress disorder (PTSD) show impaired extinction of conditioned fear, which is associated with decreased ventromedial prefrontal cortex (vmPFC) control over amygdala activity. Vagus nerve stimulation (VNS) enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here we investigated whether pairing VNS with extinction learning facilitates plasticity between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA). Rats were trained on an auditory fear conditioning task, which was followed by a retention test and 1 day of extinction training. Vagus nerve stimulation or sham-stimulation was administered concurrently with exposure to the fear-conditioned stimulus and retention of fear conditioning was tested again 24 h later. Vagus nerve stimulation-treated rats demonstrated a significant reduction in freezing after a single extinction training session similar to animals that received 5× the number of extinction pairings. To study plasticity in the IL-BLA pathway, we recorded evoked field potentials (EFPs) in the BLA in anesthetized animals 24 h after retention testing. Brief burst stimulation in the IL produced LTD in the BLA field response in fear-conditioned and sham-treated animals. In contrast, the same stimulation resulted in potentiation of the IL-BLA pathway in the VNS-treated group. The present findings suggest that VNS promotes plasticity in the IL-BLA pathway to facilitate extinction of conditioned fear responses (CFRs).
    Full-text · Article · Sep 2014
    • "Inconsistencies in the brain–behavior relationship associated with the 9/11 condition in passengers and the comparison group may also be due to greater error variance attributable to individual differences in media exposure. As noted in the introduction, studies of traumatic memory have inconsistently reported amygdalar activation , but these studies largely focus on PTSD effects (Driessen et al., 2004; Fischer et al., 1996; Hayes et al., 2012; Lanius et al., 2001; Patel et al., 2012). In the present study, we were unable to explore hypotheses related to PTSD status versus trauma exposure per se, given the restricted range of PTSD symptomatology across subjects and the lack of individuals with an active diagnosis. "
    [Show abstract] [Hide abstract] ABSTRACT: We investigated autobiographical memory in a group of passengers onboard a transatlantic flight that nearly ditched at sea. The consistency of traumatic exposure across passengers, some of whom developed posttraumatic stress disorder (PTSD), provided a unique opportunity to assess verified memory for life-threatening trauma. Using the Autobiographical Interview, which separates episodic from nonepisodic details, passengers and healthy controls (HCs) recalled three events: the airline disaster (or a highly negative event for HCs), the September 11, 2001, attacks, and a nonemotional event. All passengers showed robust mnemonic enhancement for episodic details of the airline disaster. Although neither richness nor accuracy of traumatic recollection was related to PTSD, production of nonepisodic details for traumatic and nontraumatic events was elevated in PTSD passengers. These findings indicate a robust mnemonic enhancement for trauma that is not specific to PTSD. Rather, PTSD is associated with altered cognitive control operations that affect autobiographical memory in general.
    Article · Aug 2014
Show more

Supplementary resources