Quantitative meta-analysis of neural activity in posttraumatic stress disorder

  • Jasmeet P Hayes1, 2, 3Email author,

    Affiliated with

    • Scott M Hayes2, 3, 4 and

      Affiliated with

      • Amanda M Mikedis1, 2

        Affiliated with

        Biology of Mood & Anxiety Disorders20122:9

        DOI: 10.1186/2045-5380-2-9

        Received: 16 February 2012

        Accepted: 26 April 2012

        Published: 18 May 2012

        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 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.

        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 functioning. With the growing interest in PTSD due in part to its high prevalence among veterans of the Iraq and Afghanistan 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 [126]. 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. Specifically, this model suggests that heightened amygdala activity gives privileged status to feared and threatening stimuli. Whereas the ventromedial prefrontal cortex would normally temper amygdala activity, abnormal function of this region reduces regulation of amygdala output [27]. Furthermore, 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 play an important role in PTSD. PTSD is more likely to develop following highly fear-provoking and life-threatening events than less intense events [29]. Influential psychological theories of PTSD have emphasized the role of fear structures and fear conditioning in the development and maintenance of the disorder [30, 31]. Furthermore, exposure therapy, which involves the principles of extinction learning [30], is one of the most effective therapeutic interventions for PTSD.

        However, fear conditioning models are limited in their ability to explain the full range of human experience and emotion. Fear conditioning can occur outside of conscious awareness, yet conscious processes such as voluntary and effortful avoidance of thoughts and memories of the trauma play a vital role in the development and maintenance of the disorder [32]. This has led to growing supposition that fear-circuitry models are unable to fully account for the heterogeneity of symptoms following a traumatic event [33] and that anxiety and fear may not be the central components in explaining PTSD symptomatology as previously believed [34]. Accordingly, the proposed revision of the Diagnostic and Statistical 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 development 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 calculates 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. Although there have been two prior functional neuroimaging 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 analysis 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 study separates 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). Furthermore, examining results from whole-brain voxel-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 comprise a significant proportion of imaging studies in PTSD, with the recognition that whole brain voxel-wise analyses represent a less biased statistical approach. Finally, we performed a separate meta-analysis to test the fear-model hypothesis that hypoactivity in the ventromedial prefrontal cortex is associated with hyperactivity in the amygdala, reflecting insufficient inhibition of prefrontal cortex over the amygdala.

        Methods

        Article selection

        Using keywords “PTSD,” “neuroimaging,” “fMRI,” and “PET,” a literature search in PubMed and Published 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 request activation coordinates [6, 10]. Case studies were excluded [39, 40] as well as studies examining PTSD and co-morbidity with other disorders, although an exception was made for major depressive disorder (MDD) because of its high co-morbidity with PTSD [13]. Based 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).
        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

        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.

        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 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 PTSD without co-morbidity vs. controls [13]). Following inclusion and exclusion of coordinates, 218 between-group activation foci remained (Table 2).
        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.

        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. Coordinates from symptom provocation and cognitive-emotional tasks were first combined to examine the neural regions involved across tasks and then were analyzed 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 coordinates were smoothed using a three-dimensional Gaussian filter and transformed into Gaussian probability distributions. These probability distributions were combined to generate whole-brain statistical maps of the ALE values on a voxel-wise basis. ALE statistics calculated the probability that at least one of the foci lay within each voxel and, therefore, the likelihood that each voxel was activated across all studies included in the analysis. The ALE statistic maps were compared with a null-distribution of random spatial associations between experiments (random-effects model) to assess for above chance clustering between experiments using a threshold at false discovery rate (FDR) corrected P < 0.05 and a cluster-extent of 100 mm3.

        To explore the hypothesis that activity in the ventromedial prefrontal cortex and the amygdala was inversely related, we first identified whole-brain studies that reported increased ventromedial prefrontal cortex activity in controls relative to PTSD patients (which would suggest that this region was hypoactive in PTSD) and also reported regions of increased activity in PTSD relative to controls. Six studies were identified that met these criteria [1, 11, 12, 2123]. A meta-analysis was performed on the coordinates from these studies for the PTSD > Control contrast. Thus, we examined the regions that were hyperactive in PTSD when the ventromedial prefrontal cortex was hypoactive. Due to the small number of studies included, the analysis was thresholded at FDR corrected P < 0.05 and a less conservative cluster-extent of 40 mm3 (i.e., 5 contiguous voxels) was used.

        Results

        Separate meta-analyses were run to examine the neural activity across and within symptom provocation and cognitive-emotional tasks in PTSD. Because of the variability in naming conventions of medial prefrontal cortex regions across different studies, activated regions are listed in the text and tables both by their structure specific 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 studies were collapsed across task type (i.e., symptom provocation 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 prefrontal cortex activity was observed when ROI studies were included (Figure 1)B.
        Table 3

        Between-group comparison of activity across symptom provocation and cognitive-emotional studies

        Region

        Hemisphere

        Talairach

        BA

        Volume (mm3)

          

        x

        y

        z

          

        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

        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 mm3. ACC = anterior cingulate cortex, BA = Brodmann area, dmPFC = dorsomedial prefrontal cortex, L = left, R = right, vmPFC = ventromedial prefrontal cortex.

        http://static-content.springer.com/image/art%3A10.1186%2F2045-5380-2-9/MediaObjects/13587_2012_21_Fig1_HTML.jpg
        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.

        Notably, there were several regions of hypoactivation in PTSD relative to controls including the medial frontal gyrus (ventromedial prefrontal cortex; Figure 1B), thalamus, right inferior frontal gyrus (Figure 1B), and right middle temporal gyrus. When ROI studies were included, the results remained consistent with additional activity observed in the pregenual anterior cingulate cortex (Table 3).

        Symptom provocation studies

        A meta-analysis of symptom provocation designs was conducted to reveal the regions that were involved in reliving one’s traumatic event (Table 4). The regions consistently 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 provocation and cognitive-emotional studies.
        Table 4

        Between-group comparison results of symptom provocation articles and cognitive-emotional articles

        Region

        Hemisphere

        Talairach

        BA

        Volume (mm3)

          

        x

        y

        z

          

        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 mm3. ACC = anterior cingulate cortex, BA = Brodman area, dmPFC = dorsomedial prefrontal cortex, L = left, R = right, vmPFC = ventromedial prefrontal cortex.

        http://static-content.springer.com/image/art%3A10.1186%2F2045-5380-2-9/MediaObjects/13587_2012_21_Fig2_HTML.jpg
        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.

        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 medial 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 anterior 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 ventromedial prefrontal cortex was hypoactivated, greater amygdala activation was observed in PTSD, supporting the hypothesis that activity in the ventromedial prefrontal cortex and amygdala are inversely related. Other regions that showed increased activity included the right middle and inferior temporal gyrus, left superior temporal gyrus, bilateral precuneus, and right putamen (Table 5).
        Table 5

        Ventromedial prefrontal cortex meta-analysis results

        Region

        Hemisphere

        Talairach

        BA

        Volume (mm3)

          

        x

        y

        z

          

        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 mm3. BA = Brodmann area, L = left, R = right.

        Discussion

        The present study used quantitative meta-analysis to examine the pathophysiology of PTSD. The results confirmed involvement of a subset of regions implicated in fear-circuitry models of PTSD, including robust hyperactivity in the dorsal anterior cingulate cortex, hypoactivity in the ventromedial prefrontal cortex in PTSD, and an inverse relationship between activity in the ventromedial prefrontal cortex and amygdala. However, additional 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 cortex, supplementary motor area, and superior temporal 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]. Ultimately, the salience network helps an organism evaluate whether stimuli in the environment should be approached or avoided. Importantly, activity in this salience network is positively correlated with anxiety [43]. We propose that in PTSD, the behavioral manifestation 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 viewpoint, 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 recent data have not corroborated a cognitive versus affective dissociation. Recent reviews have called attention to the involvement of the dorsal anterior cingulate cortex in PTSD [46, 47], which may subserve learned fear, fear appraisal and expression, and sympathetic activity [48]. More broadly, dorsomedial prefrontal regions (including the dorsal anterior cingulate cortex) have been associated 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 appraisals of potential threats in the environment, whereas hypoactivity in ventromedial prefrontal regions may reflect dysfunction in emotion regulation.

        Interestingly, the present results highlight the contribution of the mid-cingulate in PTSD, adding to the growing evidence that this region plays an important role in this disorder [4951] and may be important for fear conditioning [52]. The dorsal 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 control subjects in the present meta-analysis, a more posterior region was hyperactivated only in PTSD. A previous study demonstrated that individuals with severe PTSD symptomatology activated the mid/dorsal anterior cingulate to a greater extent than controls during an emotional oddball task, suggesting that distracting stimuli are given attentional preference at the expense of a goal-relevant task in PTSD [49]. These findings provide converging 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 vulnerability to susceptibility artifact and its relatively small volume, which could account 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 previous 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 activity in PTSD. There is emerging recognition that the amygdala may play a more general role in processing ambiguous and salient stimuli in the environment [5355], of which fear may be one particularly potent instance. The amygdala, which is composed of several distinct 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 amygdala than autobiographical trauma scripts, which were often familiar and unambiguous 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 amygdala 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 majority of both symptom provocation and cognitive-emotional studies were fMRI rather than PET, suggesting that the difference is not due to imaging modality. The discrepancy in amygdala activity for cognitive-emotional and symptom provocation studies underscores 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 study, widespread hypoactivity in prefrontal 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 performed a meta-analysis that identified regions of hyperactivity within a subset of studies that showed a decrease in ventromedial prefrontal cortex activity in PTSD patients. We reasoned that under conditions of diminished ventromedial 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 prefrontal 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 information. Although the direction of this effect cannot be determined conclusively because the neural connections between the amygdala and ventromedial prefrontal cortex are bidirectional, there is a well-established literature showing the involvement of ventromedial prefrontal cortex in regulatory control across species [58]. It is important 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 functions. 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 activation 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 prefrontal cortex consistent across task type, underscoring its hypothesized role in regulatory control.

        Importantly, additional prefrontal cortex regions such as the inferior frontal gyrus were hypoactivated in PTSD. This finding is notable as previous work has implicated the role of inferior frontal gyrus in emotion regulation, including inhibition from emotional distraction [60] and emotional thought suppression [61]. Moreover, the inferior frontal gyrus is purported to be involved in a network of lateral prefrontal cortex regions involved in changing one’s negative thoughts to reduce the impact of negative feelings (i.e., cognitive reappraisal) [62]. Although 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 PTSD highlight the role of negative appraisals and emotion regulation in the etiology and maintenance of PTSD. One of the most successful psychosocial interventions for PTSD, cognitive processing therapy, is based upon the notion that faulty cognitions and interpretation surrounding the traumatic event interferes with the natural recovery process after a trauma [63]. For example, a female rape victim who misattributes blame to herself for attending a party where the rape occurred may then mistrust her decisions in every aspect of her life, leading to experiential avoidance and withdrawal 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]. Cognitive 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 individuals who benefitted from cognitive processing therapy recruit the inferior frontal gyrus to a greater extent compared 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 analyses. Although the literature search started with 79 studies, the exclusion of studies that did not include stereotaxic coordinates likely reduced our power to detect 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, was observed in the PTSD group using a less stringent cluster threshold (FDR corrected, P < 0.05, cluster-extent = 24 mm3). 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 convincing evidence that the hippocampus 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 literature examining learning and memory in PTSD, which may clarify the role of hippocampus given that these types of paradigms traditionally activate the hippocampus in healthy individuals.

        Finally, working with a limited sample required inclusion 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 include 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 studies that were diverse in terms of functional imaging modality, study design, and PTSD trauma type. The results provide evidence for hyperactivation of regions important for vigilance and salience detection, and hypoactivation of regulatory networks engaged in regulation of autonomic arousal and cognition. The key salience network regions that appear to be important in PTSD include the dorsomedial prefrontal cortex (including mid/dorsal anterior cingulate cortex), supplementary motor 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 putatively 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 treatment of PTSD.

        Declarations

        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 analysis, interpretation of the data, writing of the report, or approval of the paper.

        Authors’ Affiliations

        (1)
        National Center for PTSD, VA Boston Healthcare System
        (2)
        Neuroimaging Research Center, VA Boston Healthcare System
        (3)
        Department of Psychiatry, Boston University School of Medicine
        (4)
        Memory Disorders Research Center, VA Boston Healthcare System and Boston University School of Medicine

        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, 156:1787–1795.PubMed
        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, 45:806–816.PubMedView Article
        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, 55:612–620.PubMedView Article
        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, 53:879–889.PubMedView Article
        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, 57:832–840.PubMedView Article
        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.PubMedView Article
        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, 29:517–523.PubMedView Article
        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, 119:241–247.PubMedView Article
        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, 68:433–441.PubMedView Article
        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, 70:27–31.PubMedView Article
        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, 1144:165–174.PubMedView Article
        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, 42:268–277.PubMedView Article
        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, 155:45–56.View Article
        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, 52:305–311.PubMedView Article
        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, 158:1920–1922.PubMedView Article
        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, 53:204–210.PubMedView Article
        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, 63:184–192.PubMedView Article
        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, 57:464–473.PubMedView Article
        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, 47:769–776.PubMedView Article
        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, 26:813–821.PubMedView Article
        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, 156:575–584.PubMed
        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, 61:168–176.PubMedView Article
        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, 62:273–281.PubMedView Article
        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, 171:44–53.View Article
        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, 69:98–107.View Article
        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, 29:347–357.PubMedView Article
        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, 60:376–382.PubMedView Article
        28. LeDoux JE: Emotion circuits in the brain. Annu Rev Neurosci 2000, 23:155–184.PubMedView Article
        29. Kilpatrick DG, Resnick HS, Acierno R: Should PTSD Criterion A be retained? J Trauma Stress 2009, 22:374–383.PubMedView Article
        30. Foa EB, Kozak MJ: Emotional processing of fear: Exposure to corrective information. Psychol Bull 1986, 99:20–35.PubMedView Article
        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. In Trauma and its Wake: The Study and Treatment of Post-traumatic Stress Disorder. Edited by: Bristol FC. Brunner/Mazel, PA; 1985:257–294.
        32. Ehlers A, Mayou RA, Bryant B: Psychological predictors of chronic posttraumatic stress disorder after motor vehicle accidents. J Abnorm Psychol 1998, 107:508–519.PubMedView Article
        33. Suvak MK, Barrett LF: Considering PTSD from the perspective of brain processes: A psychological construction approach. J Trauma Stress 2011, 24:3–24.PubMedView Article
        34. Resick PA, Miller MW: Posttraumatic stress disorder: Anxiety or traumatic stress disorder? J Trauma Stress 2009, 22:384–390.PubMedView Article
        35. Friedman MJ, Resick PA, Bryant RA, Brewin CR: Considering PTSD for DSM 5. Depress Anxiety 2011, 28:750–769.PubMedView Article
        36. Turkeltaub PE, Eden GF, Jones KM, Zeffiro TA: Meta-analysis of the functional neuroanatomy of single-word reading: Method and validation. Neuroimage 2002, 16:765–780.PubMedView Article
        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, 164:1476–1488.PubMedView Article
        38. Simmons AN, Matthews SC: Neural circuitry of PTSD with or without mild traumatic brain injury: A meta-analysis. Neuropharmacology 2012, 62:598–606.PubMedView Article
        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, 1:1–10.
        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, 160:667–669.PubMedView Article
        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, 51:677–683.PubMedView Article
        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, 87:615–620.PubMed
        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, 27:2349–2356.PubMedView Article
        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, 43:809–817.PubMedView Article
        45. Bush G, Luu P, Posner MI: Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci 2000, 4:215–222.PubMedView Article
        46. Hughes KC, Shin LM: Functional neuroimaging studies of post-traumatic stress disorder. Expert Rev Neurother 2011, 11:275–285.PubMedView Article
        47. Shin LM, Handwerger K: Is posttraumatic stress disorder a stress-induced fear circuitry disorder? J Trauma Stress 2009, 22:409–415.PubMedView Article
        48. Etkin A, Egner T, Kalisch R: Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci 2011, 15:85–93.PubMedView Article
        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, 172:7–15.View Article
        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, 168:979–985.PubMedView Article
        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, 66:1099–1107.PubMedView Article
        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.PubMedView Article
        53. Davis M, Whalen PJ: The amygdala: Vigilance and emotion. Mol Psychiatr 2001, 6:13–34.View Article
        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.PubMedView Article
        55. Whalen PJ: Fear, vigilance, and ambiguity: Initial neuroimaging studies of the human amygdala. Curr Dir Psychol Sci 1998, 7:177–188.View Article
        56. Blackford JU, Buckholtz JW, Avery SN, Zald DH: A unique role for the human amygdala in novelty detection. Neuroimage 2010, 50:1188–1193.PubMedView Article
        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, 20:929–940.PubMedView Article
        58. Quirk GJ, Beer JS: Prefrontal involvement in the regulation of emotion: convergence of rat and human studies. Curr Opin Neurobiol 2006, 16:723–727.PubMedView Article
        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, 162:59–72.View Article
        60. Dolcos F, McCarthy G: Brain systems mediating cognitive interference by emotional distraction. J Neurosci 2006, 26:2072–2079.PubMedView Article
        61. Depue B, Curran T, Banich M: Prefrontal regions orchestrate suppression of emotional memories via a two-phase process. Science 2007, 317:215–219.PubMedView Article
        62. Ochsner KN: For better or for worse: Neural systems supporting the cognitive down- and up-regulation of emotion. Neuroimage 2004, 23:483–499.PubMedView Article
        63. Resick PA, Monson C, Chard K: Cognitive processing therapy: Veteran/military version. Department of Veterans' Affairs, Washington DC; 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, 17:439–452.View Article
        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.PubMedView Article
        66. Ulrich-Lai YM, Herman JP: Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 2009, 10:397–409.PubMedView Article
        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, 45:660–669.PubMedView Article

        Copyright

        © Hayes et al.; licensee BioMed Central Ltd. 2012

        This article is published under license to 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.

        Advertisement