Notwithstanding some discrepancy between results from neuroimaging studies of symptom provocation in posttraumatic stress disorder (PTSD), there is broad agreement as to the neural circuit underlying this disorder. It is thought to be characterized by an exaggerated amygdalar and decreased medial prefrontal activation to which the elevated anxiety state and concomitant inadequate emotional regulation are attributed. However, the proposed circuit falls short of accounting for the main symptom, unique among anxiety disorders to PTSD, namely, reexperiencing the precipitating event in the form of recurrent, distressing images and recollections. Owing to the technical demands, neuroimaging studies are usually carried out with small sample sizes. A meta-analysis of their findings is more likely to cast light on the involved cortical areas. Coordinate-based meta-analyses employing ES-SDM (Effect Size Signed Differential Mapping) were carried out on 19 studies with 274 PTSD patients. Thirteen of the studies included 145 trauma-exposed control participants. Comparisons between reactions to trauma-related stimuli and a control condition and group comparison of reactions to the trauma-related stimuli were submitted to meta-analysis. Compared to controls and the neutral condition, PTSD patients showed significant activation of the mid-line retrosplenial cortex and precuneus in response to trauma-related stimuli. These midline areas have been implicated in self-referential processing and salient autobiographical memory. PTSD patients also evidenced hyperactivation of the pregenual/anterior cingulate gyrus and bilateral amygdala to trauma-relevant, compared to neutral, stimuli. Patients showed significantly less activation than controls in sensory association areas such as the bilateral temporal gyri and extrastriate area which may indicate that the patients’ attention was diverted from the presented stimuli by being focused on the elicited trauma memory. Being involved in associative learning and priming, the retrosplenial cortex may have an important function in relation to trauma memory, in particular, the intrusive reexperiencing of the traumatic event.
Citation: Sartory G, Cwik J, Knuppertz H, Schürholt B, Lebens M, et al. (2013) In Search of the Trauma Memory: A Meta-Analysis of Functional Neuroimaging Studies of Symptom Provocation in Posttraumatic Stress Disorder (PTSD). PLoS ONE 8(3): e58150. doi:10.1371/journal.pone.0058150
Editor: Carles Soriano-Mas, Bellvitge Biomedical Research Institute-IDIBELL, Spain
Received: October 23, 2012; Accepted: January 31, 2013; Published: March 25, 2013
Copyright: © 2013 Sartory et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was funded by the University of Wuppertal. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Posttraumatic stress disorder (PTSD) is a severe anxiety disorder following a traumatic event. The diagnostic criteria are re-experiencing of the trauma, autonomic reactivity to and avoidance of trauma-related cues and elevated arousal . The neuronal circuit proposed to underlie PTSD implicates hyperresponsivity of the amygdala, whose activity cannot be regulated by concomitantly hyporeactive medial prefrontal and anterior cingulate cortex (ACC), and a deficient hippocampal function preventing the re-assessment of the traumatic event –. The model inspired neuroimaging studies using SPECT, PET and fMRI to uncover the neuronal response to symptom provocation, i.e., the presentation of trauma reminders such as pictures, sounds or script-driven imagery. To data, however, results have been only partly convergent and there have been findings of additionally activated areas which did not form part of the proposed circuit –.
Having been shown to be essential for fear conditioning , the amygdala was a frequent target of hypothesis-guided region-of-interest (ROI) analyses in neuroimaging studies of PTSD. In most studies, the amygdala showed hyperresponsivity during presentation of trauma narratives –, to combat sounds –, and combat pictures  in war veterans with PTSD. But there are also a number of reports of the amygdala showing no response to trauma-related cues (e.g. –) or even hyporesponsivity . A hyperreactive amygdala is, in any case, not specific to PTSD but has also been found in other anxiety disorders , with generally aversive stimuli  and even during appetitive learning .
Medial prefrontal cortex/ACC is thought to have a regulatory function in emotional processing  which is impaired in PTSD. Consistent with this hypothesis, ACC was found to be less activated in PTSD patients than controls during symptom provocation in a number of studies , –. There were some exceptions, however , . Compared to other anxiety disorders, hypoactivation in the dorsal and the rostral cingulate and ventromedial prefrontal cortex was specific to PTSD  but similar results were found in depression (e.g. ).
Results regarding hippocampal/parahippocampal involvement have been similarly inconsistent. Bremner et al.  found decreased hippocampal activation during script driven imagery in survivors of childhood sexual abuse and there are reports of impaired learning in PTSD patients , . Conversely, other studies found evidence of increased hippocampal activation in PTSD (e.g. ) or could not replicate the finding of an impaired memory function .
Various factors have been suggested to account for the inconsistent results. There is considerable heterogeneity among PTSD patients regarding comorbid disorders. Nearly 50% of PTSD patients develop depression and almost as many suffer from alcohol/drug abuse and dependence . The latter are particularly prevalent among long-term PTSD patients such as war veterans and victims of childhood abuse. Depression could account for hyporeactivity of the medial frontal/ACC area and alcohol/drug abuse for the abnormal functioning of the hippocampus.
It is noteworthy that the clinical features which most clearly distinguish PTSD from other anxiety disorders namely, reexperiencing and flashbacks, are not accounted for by the hypothesized neuronal circuitry. Reexperiencing has been proposed as the result of associative learning of the event with concomitant environmental stimuli which are subsequently able to evoke the trauma memory. The sudden occurrence of flashbacks has been explained by priming, an increased sensitization to features of trauma-related and associated stimuli –. These processes require activation of associative cortical areas which has been reported in a number of studies , , ,  but, with a notable exception , have not been included in the hypothesized underlying neuronal circuit.
Owing to the considerable technical demands, only a small number of patients were included in most of the neuroimaging studies. By combining studies, meta-analyses may provide more reliable results. A number of meta-analyses of functional neuroimaging studies in PTSD have been carried out recently , –. Etkin and Wager  compared PTSD with other anxiety disorders and found amygdalar hyperactivation in all disorders but dorsal and rostral cingulate hypoactivation only in PTSD. Assuming that PTSD results in fundamental alteration of brain function, Patel et al.  and Simmons and Matthews  carried out meta-analyses across a variety of conditions and cognitive tasks. Patel et al.  confirmed the activation pattern reported by Etkin and Wager  and found additional hyperactivation in the hippocampus. Simmon and Matthews’ study  aimed at disentangling PTSD from mild traumatic brain injury. The authors found a potential overlap between the two disorders in findings on the middle frontal gyrus and also noted that some of the findings were task-specific. Finally, Haynes et al.  carried out separate meta-analyses of symptom provocation and cognitive task studies. Symptom provocation resulted in hyperactivity of mid- and dorsal anterior cingulate and hypoactivity of the medial frontal gyrus in PTSD patients.
The previous meta-analyses did not include all neuroimaging studies of symptom provocation. To date there are additional studies with considerably larger samples than were included so far. A further meta-analysis therefore appeared justified. Only symptom provocation studies have been included in the present meta-analyses, i.e. presentation of trauma related scripts or stimuli compared to a neutral condition. In addition, a further type of meta-analysis was employed which may be more appropriate to a combined analysis of widely varying samples.
Previous studies employed activation likelihood estimation (ALE) –, the first method based on the regional likelihood of reported peak locations of significant activation clusters. A more recently developed coordinate-based method called signed differential mapping (SDM)  improved on the previous method by accounting for both hyper- and hypoactivation. A further development, Effect Size-SDM (ES-SDM)  combines peak coordinates and statistical parametric maps. This has improved both the overlap and sensitivity, while protecting against false negatives. ES-SDM was found to be superior to ALE in these respects .
In the present study, an ES-SDM meta-analysis was carried out comparing PTSD patients and trauma-exposed controls with respect to their pattern of neural activation to trauma-related stimuli. Further analyses compared reactions to trauma-related stimuli with the neutral condition within the patient and control group separately. We expected to confirm the hypothesized neuronal circuit and additionally, to find activation of associative cortical areas in patients but not in controls.
Materials and Methods
A literature search was conducted to identify fMRI, PET and SPECT studies of symptom provocation in traumatized individuals. The search for neuroimaging data was conducted on Medline, PubMed and Psychinfo in mid-January 2012. The search terms were: PTSD or ASD (acute stress disorder) + symptom provocation + PET (positron emission tomography), SPECT (single photon emission computerized tomography) or fMRI (functional magnetic resonance imaging). In addition, the reference lists of resulting articles were reviewed for relevant studies not identified by the initial database search. The search yielded 24 studies from which a subset was selected according to the following inclusion criteria: (1) PTSD or ASD diagnosis in the patient group, (2) symptom provocation, i.e., the use of trauma-related stimuli and a control condition.
The studies were additionally checked to ensure that the reported results were from independent samples. If samples were found to be overlapping, only data from the most recent report were included. Nineteen studies with a total of 274 patients met the inclusion criteria, 13 of which also presented data on a total of 145 trauma-exposed controls. A list of the studies with design characteristics is shown in table 1.
Table 1. Studies included in the meta-analyses with a description of the participants (men/women, index trauma, mean age (SD)) and method of symptom provocation.doi:10.1371/journal.pone.0058150.t001
Studies presenting threatening stimuli not directly related to the trauma, such as angry faces, or cognitive tasks were not included in the meta-analysis. Symptom provocation studies were included irrespective of whether stimuli were autobiographical or generic, e.g. combat noise in veterans. In case of multiple symptom provocation methods, preference was given to results from the presentation of pictures followed by imagery and trauma scripts. As to trauma pictures, only data from presentations above the perceptual threshold were included. Thus, in Hendler et al.’s study , only the response to pictures presented for 80 ms was included. Only one data set per study was included unless there were independent samples of patients, for example, PTSD patients with and without dissociation .
Three meta-analyses were performed comparing (1) PTSD patients with controls with regard to reactions to trauma-related stimuli, (2) reactions to the trauma-related with the neutral condition in PTSD and (3) controls, respectively. The meta-analyses were performed using ES-SDM (Effect Size Signed Differential Mapping) , – (http://www.sdmproject.com/software). The analysis method combines both peak coordinates and statistical parametric maps while also using standard effect size and variance-based meta-analytic calculations. First, reported peak coordinates were used to recreate a statistical map of the differences between groups/conditions for each study. MNI coordinates were converted into Talairach coordinates. Second, meta-analytic maps were obtained by voxel-wise calculation of the statistics of interest from the study maps, weighted by the squared root of the sample size of each study so that studies with large sample sizes contributed more. Additional control for heterogeneity between studies was provided by adopting a random-effect model. ES- SDM calculates both positive and negative differences between comparison conditions. A correction threshold of p<.005 and a cluster-size >10 voxel was applied to the results. A threshold of uncorrected p<.005 was reported to balance sensitivity and specificity optimally and to be an approximate equivalent to a corrected p<.05 in ES-DSM .
Peak coordinates were submitted to MRICroGL (http://www.cabiatl.com/mricrogl/) which provided templates to visualize the results.
As shown in table 2, the comparison between PTSD patients and controls with respect to their response to trauma-related stimuli showed that patients exhibited greater activation than controls in the mid-line anterior cingulate cortex, retrosplenial cortex and precuneus (Fig. 1). Greater activation was also evident in the right middle frontal gyrus and superior parietal lobe as well as the left precentral and angular gyrus. In contrast, as shown in table 3, patients showed less activation than controls in superior and middle temporal gyrus, postcentral and mid-occipital gyrus (Fig. 2). When comparing trauma-related stimuli with the control condition (Table 4), patients exhibited significantly greater activation in the mid-line pregenual and retrosplenial cortex and precuneus (Fig. 3) as well as in the bilateral amygdala, mid-occipital and angular gyrus. In controls (Table 5), the most extensive activations were evident in midline superior prefrontal cortex together with left thalamus and bilateral dorsal cingulate gyrus, right cuneus and declive (Fig. 4). Comparing the two conditions, neither group showed significantly decreased activation.
Figure 1. Activation map of patients contrasted with controls.
Significant activations of PTSD patients compared to trauma-exposed controls in response to trauma-related stimuli. (Numbers in brackets indicate Brodmann areas and coordinates of the peak voxel are in Talairach space).doi:10.1371/journal.pone.0058150.g001
Figure 2. Activation map of controls contrasted with patients.
Significantly increased (red) and decreased (blue) activations in PTSD patients compared to trauma-exposed controls in response to trauma-related stimuli. (Numbers in brackets indicate Brodmann areas and coordinates of the peak voxel are in Talairach space).doi:10.1371/journal.pone.0058150.g002
Figure 3. Activation map of patients.
Significant activations of PTSD patients in response to trauma-related stimuli as compared to a neutral condition. (Numbers in brackets indicate Brodmann areas and coordinates of the peak voxel are in Talairach space).doi:10.1371/journal.pone.0058150.g003
Figure 4. Activation map of controls.
Significant activations of trauma-exposed controls in response to trauma-related stimuli as compared to a neutral condition. (Numbers in brackets indicate Brodmann areas and coordinates of the peak voxel are in Talairach space).doi:10.1371/journal.pone.0058150.g004
Table 2. Comparison between PTSD patients and trauma-exposed controls in respect to their response to trauma-related stimuli (PTSD patients > controls).doi:10.1371/journal.pone.0058150.t002
Table 3. Comparison between PTSD patients and trauma-exposed controls in respect to trauma-related stimuli (PTSD patients < controls).doi:10.1371/journal.pone.0058150.t003
Table 4. PTSD patients: Comparison of reactions to trauma-related stimulation (symptom provocation) with a control condition.doi:10.1371/journal.pone.0058150.t004
The coordinate-based meta-analysis of neural activation during trauma-related stimulation partly confirms and partly contradicts the current model of brain circuitry of PTSD. Furthermore, important additional areas were shown to be activated that hitherto have been neglected in the modeling of trauma symptoms. In patients, results from the between group and between condition analyses were widely overlapping.
Compared to controls and a control condition, PTSD patients showed significant activation of the mid-line retrosplenial cortex, precuneus, anterior cingulate gyrus as well as the left angular gyrus. Little attention has so far been paid to the role of activation of medial posterior aspects namely, retrosplenial cortex and precuneus in PTSD. The reevaluation of research into mid-line areas has recently produced new insights that are likely to be of relevance for our understanding of - among anxiety disorders – the unique and most salient of all PTSD symptoms namely, reexperiencing.
Activation of cortical midline structures during resting, i.e., the absence of stimulus-driven processing, has been considered to be indicative of the baseline of brain functioning  or a default mode network –. The use of self-related tasks during neuroimaging, e.g. when participants evaluated whether statements could be attributed to themselves – has, however, led to the suggestion that these areas subserve self-referential processing. Surveying the experimental evidence led Northoff and Bermpohl  to hypothesize a system whereby anterior midline areas are involved in the representation, evaluation and monitoring and posterior areas in the integration of self-referential stimuli and autobiographical memory. These processes appear to be independent of sensory modality and domain and were reported to be activated by tasks such as viewing a video of a previously experienced bank robbery  or hearing a familiar as compared to an unfamiliar voice . Furthermore, recollecting familiar faces or events involving the self could be shown to result in activation of the retrosplenial cortex –. Meta-analyses of neuroimaging findings of autobiographical memory – confirmed the implication of this area. Further corroboration results from cognitive impairment of episodic memory and autobiographical amnesia which have been reported to be the result of damage to the retrosplenial cortex –.
Activation of the retrosplenial cortex has also been shown to be essential for successful associative learning, i.e., forming of associations between multiple sensory stimuli in rodents  and, similarly in humans, for learning contextual associations and priming –. These processes are likely to be required in the formation of autobiographical memory and self-referential processing. Contextual associations and priming are considered to bring about reexperiencing of the traumatic event in PTSD – and could, therefore, also account for the activation of the retrosplenial cortex during symptom provocation procedures.
It is noteworthy that control participants failed to show significant activation of the retrosplenial cortex although they, too, were confronted with material of self-relevance. Two reasons could account for this group difference. PTSD patients may have shown greater activation because the trauma memory was more recent for them owing to their reexperiencing the event. The group difference is, however, more likely to be due to the trauma-related material being more salient for patients than controls. As a rule, the trauma-related material evoked more fear in patients than controls (e.g. ) and can therefore be considered to be more salient for the former. Reviewing the literature of retrosplenial cortex and emotion, Maddock  found that the former was more strongly activated by salient stimuli from autobiographical memory.
The present meta-analysis also revealed activation of the precuneus, the medial extent of area 7, viz. the anterior portion, in PTSD patients during symptom provocation and in comparison with control participants. Activation of the precuneus was found to be correlated with that of area 31 of the retrosplenial cortex  and reported to have a central role in a wide spectrum of highly integrated tasks. Reviewing the literature, Cavanna and Trimble  reported involvement in visual-spatial imagery, episodic memory retrieval and self-processing operations such as first-person perspective taking. The authors pointed out that the neuroimaging data suggest a dissociation of function within the precuneus with the anterior region being involved in self-referential processing and the posterior region subserving episodic memory retrieval. Comparing the BOLD response to pictures that were either self-referential or familiar, Sajonz et al.  confirmed that the former elicited activation in anterior and the latter in posterior portions of the precuneus. The present result of activation of the anterior precuneus would therefore suggest self-referential retrieval of trauma-related memories during symptom provocation in patients. Together with the retrosplenial cortex this area could play an essential role in the intrusive and distressing reexperiencing of the traumatic event in PTSD.
The left anterior cingulate gyrus is also considered to be part of the circuit subserving self-referential processing , , in particular, with regard to the judgment whether stimuli were self-referential –. This area has therefore been accorded a monitoring role . Summarizing, findings of the activated midline structures to trauma-related material can be considered to be indicative of the adjudgment and retrieval of events with high self-relevance in PTSD patients.
The left gyrus angularis (area 39) was significantly activated during trauma-related stimulation in patients and significantly more so than in controls. The temporo-parietal junction is considered a high level centre integrating multisensory, sensorimotor and cognitive function  and has been accorded the role of a prominent node in the default/autobiographical memory network –. Morey et al.  reported a positive correlation between activation of this area and a global symptom severity score which leaves the question open as to the relationship to particular symptoms. It is conceivable that activation of the gyrus angularis induces dissociation. Stimulation of this area has been shown to induce out-of-the-body experiences  which are sometimes reported by PTSD patients as occurring during the most intensely stressful time of the traumatic event. The experience is usually accompanied by dissociation, mental and emotional disengagement.
Patients exhibited greater activation than controls in the left caudate body and dorsal anterior cingulate cortex (ACC). The latter has been found to be part of a network for salience processing  and is thought to form an essential node within the salience network . The caudate nucleus is part of the system involved in motor function. Together with the activated frontal eye field (6) and the dorsal ACC, it is likely to form a circuit which gives rise to eye movement which, in turn, is part of the orienting reaction elicited by the fear evoking stimuli in patients.
The exaggerated amygdalar response has been found by the majority of neuroimaging studies of PTSD but also of other anxiety disorders . Including only whole brain analyses, a recent meta-analysis of neural correlates of basic emotions found fear to be consistently activating both amygdalae and insula whereas responsivity of the latter was also involved in other emotions such as anger and disgust . Unlike in these previous reports, no increased activation of insula was found among the present results. Both the previous meta-analyses included studies which employed a variety of emotion-related processes and cognitive tasks and are not, therefore, directly comparable with the narrow focus on symptom provocation of the present meta-analysis.
PTSD patients showed less activation than control participants with regard to lateral and dorsal sensory association areas namely, the left mid and right superior temporal gyrus, the left mid occipital gyrus and the bi-lateral postcentral gyrus. In two thirds of the studies stimuli used for symptom provocation consisted of personalized scripts of the traumatic event and in the remaining ones of pictures and sounds such as combat noise. Apart from being autobiographically relevant, trauma-related stimuli were generally unpleasant and arousing. Activation of the sensory association areas in controls suggests increased attention and processing of the presented material. It is conceivable that the self-referential processing in patients, unlike in controls, comes at a cost and has an inhibiting effect on the capacity to process concomitant environmental stimuli.
The present results failed to support the hypothesized inhibition of anterior cingulate cortex (ACC) activation. The area is thought to play an important role in emotional regulation and failure to do so in PTSD. The effect does not appear to be due to stimulus modality. Some studies reporting reduced activation presented pictures , ,  and others personalized scripts , , . But as many studies reported increased ACC activation with pictures , ,  as with personalized scripts , , –. As PTSD is a heterogeneous disorder, ACC activation could be related to particular symptoms. Morey et al.  found increased ACC activation to be positively correlated with PTSD severity while Lanius et al.  reported increased ACC activation in PTSD patients suffering from flash-backs but not in patients with dissociation. In contrast, Hopper et al.  found decreased ACC activation to be related to reexperiencing. Decreased ACC activation may not be specific to anxiety disorders as it has also been found in depression , a frequent comorbid disorder of PTSD.
Both patients and controls showed significant activation of the medial superior prefrontal cortex (BA 9), patients more so than controls and the latter in response to trauma-related compared to neutral stimuli. It has been suggested that this area is associated with theory of mind, the ability to attribute mental states to others, and empathy, the ability to infer emotional experiences –. As is known from clinical experience, traumatic events frequently consist of witnessing injury or death of close friends, comrades or relatives. It could be speculated that the evocation of such trauma memories also elicits an empathetic response in the trauma survivors.
Among the limitations of this meta-analysis is the relatively small sample size of most of the studies included and their heterogeneity of the symptom provocation methods. Furthermore, additional analyses using control volunteers who had not undergone the traumatic event could have been informative in differentiating reactions to stimulus salience from autobiographical memory. However, as yet there are not enough studies involving unconcerned controls. Finally, heterogeneity among studies resulted from some of them reporting whole-brain analysis and others region-of-interest analysis. We hoped to compensate at least partly for the heterogeneity by using a random-effects model.
Activation of the midline retrosplenial cortex and precuneus in response to symptom provocation suggests enhanced self-referential processing and evocation of salient autobiographical memory in PTSD patients. This appears to come at the cost of attending to the presented stimuli, scripts, pictures, noises, as evinced by the greater activation of auditory and visual association areas in trauma-exposed controls. The results suggest that the retrosplenial cortex has an important role in establishing and maintaining the trauma memory. Furthermore, its implication in associative learning and priming makes the retrosplenial cortex a likely candidate for giving rise to reexperiencing and intrusive memories of the precipitating traumatic event.
Conceived and designed the experiments: GS ML. Analyzed the data: JC BS HK. Contributed reagents/materials/analysis tools: RS. Wrote the paper: GS RJS.
- 1. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorder, 4th edition, text revision. Washington, DC: American Psychiatric Association.
- 2. Shin LM, Rauch SL, Pitman RK (2006) Amygdala, medial prefrontal cortex, and hippocampal funktion in PTSD. Ann New York Acad Sci 1071: 67–79. doi: 10.1196/annals.1364.007
- 3. Rauch SL, Shin LM, Phelps EA (2006) Neurocircuitry models of posttraumatic stress disorder and extinction: Human neuroimaging research- past, present, and future. Biol Psychiatry 60: 376–382. doi: 10.1016/j.biopsych.2006.06.004
- 4. Lanius RA, Bluhm R, Lanius U, Pain C (2006) A review of neuroimaging studies in PTSD: Heterogeneity of response to symptom provocation. J Psychiatric Res 40: 709–729. doi: 10.1016/j.jpsychires.2005.07.007
- 5. Garfinkel SN, Liberzon I (2009) Neurobiology of PTSD: A review of neuroimaging findings. Psychiatric Ann 39: 370–381. doi: 10.3928/00485713-20090527-01
- 6. Hughes KC, Shin LM (2011) Functional neuroimaging studies of post-traumatic stress disorder. Expert Reviews Neurother 11: 275–285. doi: 10.1586/ern.10.198
- 7. LeDoux JE (2000) Emotion Circuits in the Brain. Ann Rev Neurosci 23: 155–184. doi: 10.1146/annurev.neuro.23.1.155
- 8. Rauch SL, van der Kolk BA, Fisler RE, Alpert NM, Orr SP, et al. (1996) A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Arch Gen Psychiatry 53: 380–387. doi: 10.1001/archpsyc.1996.01830050014003
- 9. Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, et al. (2004) 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 61: 168–176. doi: 10.1001/archpsyc.61.2.168
- 10. Liberzon I, Taylor SF, Amdur R, Jung TD, Chamberlain KR, et al. (1999) Brain activation in PTSD in response to trauma-related stimuli. Biol Psychiatry 45: 817–826. doi: 10.1016/s0006-3223(98)00246-7
- 11. Pissiota A, Frans Ö, Fernandez M, von Knorring L, Fischer H, et al. (2002) Neurofunctional correlates of posttraumatic stress disorder: A PET symptom provocation study. Eur Arch Psychiatry Clin Neurosci 252: 68–75. doi: 10.1007/s004060200014
- 12. Hendler T, Rotshtein P, Yeshurun Y, Weizmann T, Kahn I, et al. (2003) Sensing the invisible: differential sensitivity of visual cortex and amygdala to traumatic context. NeuroImage 19: 587–600. doi: 10.1016/s1053-8119(03)00141-1
- 13. Lanius RA, Williamson PC, Densmore M, Boksman K, Gupta MA, et al. (2001) Neural correlates of traumatic memories in posttraumatic stress disorder: A functional MRI investigation. Am J Psychiatry 158: 1920–1922. doi: 10.1176/appi.ajp.158.11.1920
- 14. Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, et al. (1999) Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: A PET investigation. Am J Psychiatry 156: 575–583.
- 15. Britton JC, Phan KL, Taylor SF, Fig LM, Liberzon I (2005) Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery. Biol Psychiatry 57: 832–840. doi: 10.1016/j.biopsych.2004.12.025
- 16. Etkin A, Wager TD (2007) Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 164: 1476–1488. doi: 10.1176/appi.ajp.2007.07030504
- 17. Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, et al. (2005) A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex response to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry 62: 273–281. doi: 10.1001/archpsyc.62.3.273
- 18. McDonald RJ, White NM (1993) A triple dissociation of memory systems: Hippocampus, amygdala, and dorsal striatum. Behav Neurosci 107: 3–22. doi: 10.1037//0735-7044.107.1.3
- 19. Bush G, Luu P, Posner MI (2000) Cognitive and emotional influence in anterior cingulated cortex. Trends Cog Sci 4: 215–223. doi: 10.1016/s1364-6613(00)01483-2
- 20. Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, et al. (1997a) A positron emission tomographic study of symptom provocation in PTSD. Ann New York Acad Sci 821: 521–523. doi: 10.1111/j.1749-6632.1997.tb48320.x
- 21. Bremner JD, Narayan M, Staib LH, Southwick SM, McGlashan T, et al. (1999b) Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Am J Psychiatry 156: 1787–1795. doi: 10.1016/s0006-3223(02)01891-7
- 22. Yang P, Wu MT, Hsu CC, Ker JH (2004) Evidence of early neurobiological alternations in adolescents with posttraumatic stress disorder: a functional MRI study. Neurosci Letters 370: 13–18. doi: 10.1016/j.neulet.2004.07.033
- 23. Williams LM, Kemp AH, Felmingham K, Barton M, Olivieri G, et al. (2006) Trauma modulates amygdala and medial prefrontal responses to consciously attended fear. NeuroImage 29: 347–357. doi: 10.1016/j.neuroimage.2005.03.047
- 24. Hou C, Liu J, Wang K, Li L, Liang M, et al. (2007) Brain responses to symptom provocation and trauma-related short-term memory recall in coal mining accident survivors with acute severe PTSD. Brain Res 1144: 165–174. doi: 10.1016/j.brainres.2007.01.089
- 25. Lanius RA, Williamson PC, Boksman K, Densmore M, Gupta M, et al. (2002) Brain activation during script-driven imagery induced dissociative responses in PTSD: A functional magnetic resonance imaging investigation. Biol. Psychiatry 52: 305–311. doi: 10.1016/s0006-3223(02)01367-7
- 26. Liotti M, Mayberg HS, McGinnis S, Brannan SL, Jerabek P (2002) Unmasking disease-specific cerebral blood flow abnormalities: Mood challenge in patients with remitted unipolar depression. Am J Psychiatry 159; 1830–1840.
- 27. Moores KA, Clark CR, McFarlane AC (2008) Abnormal recruitment of working memory updating networks during maintenance of trauma neutral information in post-traumatic stress disorder. Psychiatry Res 163, 156–170.
- 28. Osuch EA, Benson B, Geraci M, Podell D, Herscovitch P, et al. (2001) Regional cerebral blood flow correlated with flashback intensity in patients with posttraumatic stress disorder. Biol Psychiary 50: 246–253. doi: 10.1016/s0006-3223(01)01107-6
- 29. Elsesser K, Sartory G (2007) Memory performance and dysfunctional cognitions in recent trauma victims and patients with post-traumatic stress disorder. Clin Psychol Psychother 14: 464–474. doi: 10.1002/cpp.545
- 30. Kessler RC, Nelson CB, McGonagle KA, Edlund MJ, Frank RG, et al. (1995) The epidemiology of co-occurring addictive and mental disorders: Implications for prevention and service utilization. A J Orthopsychiatry 66: 17–31. doi: 10.1037/h0080151
- 31. Ehlers A, Michael T, Chen YP, Payne E, Shan S (2006) Enhanced perceptual priming for neutral stimuli in a traumatic context: A pathway to intrusive memories? Memory 14: 316–328. doi: 10.1080/09658210500305876
- 32. Ehring T, Ehlers A (2010) Enhanced priming for trauma-related words predicts posttraumatic stress disorder. J Abn Psychol 120: 234–239. doi: 10.1037/a0021080
- 33. Fischer H, Wik G, Fredrikson M (1996) Functional neuroanatomy of robbery re- experience: affective memories studied with PET. Learning Memory 7: 2081–2086. doi: 10.1097/00001756-199609020-00005
- 34. Patel R, Spreng RN, Shin LN, Girad TA (2011) Neurocircuitry models of posttraumatic stress disorder amd beyond: A meta-analysis of functional neuroimaging studies. Neuroscience and Biobehavioral Reviews 36: 2130–2142. doi: 10.1016/j.neubiorev.2012.06.003
- 35. Simmons AN (2012) Matthews (2012) Neural circuitry of PTSD with or without mild traumatic brain injury: A meta-analysis. Neuropharmacology 62: 598–606. doi: 10.1016/j.neuropharm.2011.03.016
- 36. Hayes JP, Hayes SM, Mikedis AM (2012) Quantitative meta-analysis of neural activity in posttraumatic stress disorder. Biology of Mood & Anxiety Disorders 2: 1–13. doi: 10.1186/2045-5380-2-9
- 37. Turkeltaub PE, Eden EF, Jones KM, Zeffiro TA (2002) Meta- Analysis of the functional Neuroanatomy of Single-Word Reading: Method and validation. Neuroimage 16: 765–780. doi: 10.1006/nimg.2002.1131
- 38. Eickhoff SB, Laird AR, Gefkes C, Wang LE, Zilles K, et al. (2009) Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: a random-effects approach based on empirical estimates of spatial uncertainty. Hum Brain Mapp 30: 2907–26. doi: 10.1002/hbm.20718
- 39. Radua J (2009) Mataix-Cols (2009) Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder. The British Journal of Psychiaty 195: 393–402. doi: 10.1192/bjp.bp.108.055046
- 40. Radua J, Mataix-Cols D, Phillips ML, El-Hage W, Kronhaus DM, et al.. (2012) A new meta-analytic method for neuroimaging studies that combines reported peak coordinates and statistical maps. Europ Psychiatry 10.1016/j.europsy.2011.04.001.
- 41. Lanius RA, Williamson PC, Bluhm RL, Densmore M, Boksman K, et al. (2005) Functional connectivity of dissociative responses in posttraumatic stress disorder: A functional magnetic resonance imaging investigation. Biol Psychiatry 57: 873–884. doi: 10.1016/j.biopsych.2005.01.011
- 42. Bora E, Fornito A, Radua J, Walterfang M, Seal M, et al. (2011) Neuroanatomical abnormalities in schizophrenia: A multimodel voxelwise meta-analysis and meta-regression analysis. Schizophr Res 127: 46–57. doi: 10.1016/j.schres.2010.12.020
- 43. Radua J, Mataix-Cols D (2012) Meta-analytic methods for neuroimaging data explained. Biology Mood Anx Dis 2: 1–11. doi: 10.1186/2045-5380-2-6
- 44. Gusnard DA, Raichle ME (2001) Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci 2: 685–694. doi: 10.1038/35094500
- 45. Raichle EM, McLeod AM, Snyder AZ, Powers WJ, Gusnard DA, et al. (2001) A default mode of brain function. Proc Natl Acad Sci USA 98: 676–682. doi: 10.1073/pnas.98.2.676
- 46. Buckner RL, Andrews-Hanna JR, Schacter DL (2008) The brain’s default network. Anatomy, function and relevance to disease. Ann NY Acad Sci 1124: 1–38. doi: 10.1196/annals.1440.011
- 47. Kircher TT, Senior C, Phillips ML, Benson PJ, Bulmore ET, et al. (2000) Towards a functional neuroanatomy of self processing: effects of faces and words. Brain Res Cogn Brain Res 10: 133–144. doi: 10.1016/s0926-6410(00)00036-7
- 48. Johnson SC, Baxter LC, Wilder LS, Pipe JG, Heiserman JE, et al. (2002) Neural correlates of self-reflection. Brain 125: 1808–1814. doi: 10.1093/brain/awf181
- 49. Dastjerdi M, Foster BF, Nasrullah S, Rauschecker AM, Dougherty RF, et al. (2010) Differential electrophysiological response during rest, self-referential, and non-self-referential tasks in human posteromedial cortex. PNAS 108: 3023–3028. doi: 10.1073/pnas.1017098108
- 50. Northoff G, Bermpohl F (2004) Cortical midline structures and the self. Trends Cog Sci 8: 103–107. doi: 10.1016/j.tics.2004.01.004
- 51. Shah NJ, Marshall JC, Zafiris O, Schwab A, Zillers K, et al. (2001) The neural correlates of person familiarity. A functional magnetic resonance imaging study with clinical implications. Brain 124: 804–815. doi: 10.1093/brain/124.4.804
- 52. Maddock J, Garrett AS, Buoncore MH (2001) Remembering familiar people: The posterior cingulate cortex and autobiographical memory. Neurosci 104: 667–676. doi: 10.1016/s0306-4522(01)00108-7
- 53. Summerfield JJ, Hassabis D, Maguire EA (2009) Cortical midline involvement in autobiographical memory. NeuroImage 44: 1188–1200. doi: 10.1016/j.neuroimage.2008.09.033
- 54. Trinkler I, King JA, Doedler CF, Rugg MD, Burgess N (2009) Neural bases of autobiographical support for episodic recollection of faces. Hippocampus 19: 718–730. doi: 10.1002/hipo.20556
- 55. Svoboda E, McKinnon M, Levine B (2006) The functional neuroanatomy of autobiographical memory: A meta-analysis. Neuropsychol 44: 2189–2208. doi: 10.1016/j.neuropsychologia.2006.05.023
- 56. Spreng RN, Mar RA, Kim ASN (2008) The common neural basis of autobiographical memory, prospection, navigation, theory of Mind and the default mode: A quantitative meta-analysis. Journal of Cognitive Neuroscience: 489–510.
- 57. Nestor PJ, Fryer TD, Ikeda M, Hodges JR (2003) Retrosplenial cortex (BA 29/30) hypometabolism in mild cognitive impairment (prodromal Alzheimeŕs disease). Europ J Neurosci 18: 2663–2667. doi: 10.1046/j.1460-9568.2003.02999.x
- 58. Gainotti G, Almonti S, Di Betta AM, Silveri MC (1998) Retrograde amnesia in a patient with retrosplenial tumour. Neurocase 4: 519–526. doi: 10.1080/13554799808410644
- 59. Robinson S, Keene CS, Iaccarino HF, Duan D, Bucci DJ (2011) Involvement of retrosplenial cortex in forming associations between multisensory stimuli. Behav Neurosci 125: 578–587. doi: 10.1037/a0024262
- 60. Fletcher P, Frith CD, Grasby PM, Shallice T, Frackowiak R (1995) Brain systems for encoding and retrieval of auditory-verbal memory. Brain 118: 401–416. doi: 10.1093/brain/118.2.401
- 61. Fenske MJ, Aminoff E, Gronau N, Bar M (2006) Top-down facilitation of visual object recognition: object-based and context-based contributions. Prog Brain Res 155: 3–21. doi: 10.1016/s0079-6123(06)55001-0
- 62. Eger E, Henson RN, Driver J, Dolan RJ (2007) Mechanisms of top-down facilitation in perception of visual objects studied by fMRI. Cereb Cortex 17: 2123–2133. doi: 10.1093/cercor/bhl119
- 63. Maddock RJ (1999) The retrosplenial cortex and emotion: new insights from functional neuroimaging of the human brain. TINS 22: 310–316. doi: 10.1016/s0166-2236(98)01374-5
- 64. Cauda F, Geminiani G, D´Agata F, Sacco K, Duca S, et al. (2010) Functional connectivity of the posteromedial cortex. PLOS ONE 5: e13107 doi:10.1371/journal.pone.0013107.
- 65. Cavanna AE, Trimble MR (2006) The preceuneus: a review of its functional anatomy and behavioural correlates. Medicine Brain 129: 564–583. doi: 10.1093/brain/awl004
- 66. Sajonz B, Kahnt T, Marqulies DS, Pank SQ, Wittmann A, et al. (2010) Delineating self-referential processing from episodic memory retrieval: Common and dissociable networks. Neuroimage 50: 1606–1617. doi: 10.1016/j.neuroimage.2010.01.087
- 67. Legrand D, Ruby P (2009) What is self-specific? Theoretical investigation and critical review of neuroimaging results. Psychol Rev 116: 252–282. doi: 10.1037/a0014172
- 68. McGuire PK, Solversweig DA, Frith CD (1996) Functional neuroanatomy of verbal self-monitoring. Brain 119: 907–917. doi: 10.1093/brain/119.3.907
- 69. Vogeley K, Bussfeld A, Newen A, Herrmann F, Happé F, et al. (2001) Mind reading: neural mechanisms of theory of mind and self-perspective. Neuroimage 14: 170–181. doi: 10.1006/nimg.2001.0789
- 70. Blakemore SJ, Wolpert DM, Frith CD (1998) Central cancellation of self-produced tickle sensation. Nat Neurosci 1: 635–640. doi: 10.1038/2870
- 71. Calvert GA, Campbell R, Brammer MJ (2000) Evidence from functional magnetic resonance imagery of cross modal binding in the human heteromodal cortex. Curr Biol 10: 649–657. doi: 10.1016/s0960-9822(00)00513-3
- 72. Menon V (2011) Large-scale brain networks and psychopathology: a unifying triple network model. Trend in Cognitive Sciences 15: 483–506. doi: 10.1016/j.tics.2011.08.003
- 73. Sestieri C, Corbetta M, Romani LG, Shulman GL (2011) Episodic memory retrieval, parietal cortex and the default mode network: functional and topographic analysis. The Journal of Neuroscience 23: 4407–4420. doi: 10.1523/jneurosci.3335-10.2011
- 74. Morey RA, Petty CM, Cooper DA, LaBar K, McCarthy G (2008) Neural systems for executive and emotional processing are modulated by symptoms of posttraumatic stress disorder in Iraq War veterans. Psychiatry Res 162: 59–72. doi: 10.1016/j.pscychresns.2007.07.007
- 75. Blanke O, Arzy S (2005) The out-of-the-body experience: Disturbed self-processing at the tempero-parietal junction. Neuroscientist 11: 16–24. doi: 10.1177/1073858404270885
- 76. Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, et al. (2007) Dissociable Intrinsic Connectivity Networks for salience processing and executive control. The Journal of Neuroscience 28: 2349–2356. doi: 10.1523/jneurosci.5587-06.2007
- 77. Vytal K, Hamann S (2010) Neuroimaging support for discrete neural correlates of basic emotions: A voxel-based meta-analysis. J Cog Neurosci 22: 2864–2885. doi: 10.1162/jocn.2009.21366
- 78. Bremner JD, Staib LH, Kaloupek D, Sothwick SM, Soufer R, et al. (1999a) 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 45: 806–816. doi: 10.1016/s0006-3223(98)00297-2
- 79. Hopper JW, Frewen PA, van der Kolk BA, Lanius RA (2007) Neural correlates of reexperiencing, avoidance, and dissociation in PTSD: Symptom dimensions and emotion dysregulation in response to script-driven imagery. J Traum Stress 20: 713–725. doi: 10.1002/jts.20284
- 80. Shin LM, Kosslyn SM, McNally RJ, Alpert NM, Thompson WL, et al. (1997b) Visual imagery and perception in posttraumatic stress disorder. Arch Ge. Psychiatry 54: 233–241.
- 81. Lanius RA, Frewen PA, Girotti M, Neufeld WJ, Stevens TK, et al. (2007) Neural correlates of trauma script-imagery in posttraumatic stress disorder with and without comorbid major depression: A functional MRI investigation. Psychiatry Res Neuroimaging 155: 45–56. doi: 10.1016/j.pscychresns.2006.11.006
- 82. Osuch EA, Willis MW, Bluhm R, Ursano RJ, Drevets WC (2008) Neurophysiological responses to traumatic reminders in the acute aftermath of serious motor vehicle collisions using -H2O PET. Biol Psychiatry 64: 327–335. doi: 10.1016/j.biopsych.2008.03.010
- 83. Frith CD, Frith U (2006) How we predict what other people are going to do. Brain Research 1079: 36–46. doi: 10.1016/j.brainres.2005.12.126
- 84. Hynes CA, Baird AB, Grafton ST (2006) Differential role of orbito frontal lobe in emotional versus cognitive perspective-taking. Neuropsychol 44: 374–383. doi: 10.1016/j.neuropsychologia.2005.06.011
- 85. Rankin KP, Gorno-Tempini ML, Allison SC, Stanley CM, Glenn S, et al. (2006) Structural anatomy of empathy in neurodegenerative disease. Brain 129: 2945–2956. doi: 10.1093/brain/awl254
- 86. Masten CL, Morelli SA, Eisenberger NI (2011) An fMRI investigation of empathy for ‘social pain’ and subsequent prosocial behavior. NeuroImage 55: 381–388. doi: 10.1016/j.neuroimage.2010.11.060
- 87. Driessen M, Beblo T, Mertens M, Piefke M, Rullkoetter N, et al. (2003) Posttraumatic stress disorder and fMRI activation patterns of traumatic memory in patiens with borderline personality disorder. Biol Psychiatry 55: 603–611. doi: 10.1016/j.biopsych.2003.08.018
- 88. Lanius RA, Williamson PC, Densmore M, Boksman K, Neufeld RW, et al. (2004) The nature of traumatic memories: A 4-T fMRI functional connectivity analysis. Am J Psychiatry 161: 36–44. doi: 10.1176/appi.ajp.161.1.36