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.