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
]. 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
], 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 [49
] 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 [53
], 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.
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
). 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.