The findings of the studies summarized in the previous section indicate several trends in neural correlates of PTSD, permitting us to create a model of this disorder. Two of the most recurrent findings in patients with PTSD, using PET, fMRI, and SPECT are decreased medial prefrontal cortex and increased amygdalar activation. On the other hand, inconsistent findings have been tied to regions such as the hippocampus and the adjacent parahippocampal gyrus. These inconsistencies could be the result of a wide variation of parameters in different studies, and of the complex nature of PTSD.
Altered function in the amygdala is frequently discussed in the clinical presentation of PTSD. Studies using symptom provocation paradigms and active tasks have both found an increased amygdalar activation pattern in patients with PTSD compared to healthy controls. Symptom provocation studies target the fear response mechanism, in which the amygdala is thought to play a pivotal role. Stimuli successfully used in these paradigms include combat sounds [Liberzon et al., 1999
] and images [Hendler et al., 2003
; Shin et al., 1997
], emotional faces [Rauch et al., 2000
; Shin et al., 2005
], emotional words [Protopopescu et al., 2005
], and traumatic scripts [Shin et al., 2004a
]. Furthermore, studies using active tasks found amygdala activation when subjects were instructed to perform an auditory continuous performance task [Semple et al., 2000
], explicit memory recall tasks [Shin et al., 2004b
], and active trauma recall [Driessen et al., 2004
]. On the whole, the amygdala appears to be more active in patients with PTSD. This hyperactivation is thought to be the reason for a failure of the extinction to fearful stimuli, a common component of the clinical presentation of PTSD [Bremner et al., 1995a
Another common finding in studies measuring neural activity in PTSD is a hypoactivation of the mPFC, which includes the OFC (Brodmann’s area 11), the ACC (Brodmann’s area 32), and mPFC proper (Brodmann’s areas 9 and 25). Symptom provocation paradigms that found this trend for the latter two regions in patients with PTSD made use of traumatic sounds and images [Bremner et al., 1999b
; Yang et al., 2004
], emotional faces [Shin et al., 2005
], and traumatic scripts [Bremner et al., 1999a
; Britton et al., 2005
; Lanius et al., 2001
; Liberzon et al., 2003
; Lindauer et al., 2004
; Shin et al., 1999
]. Furthermore, studies using active tasks found relative mPFC deactivation when subjects were instructed to perform an auditory continuous performance task [Semple et al., 2000
], memory tasks [Bremner et al., 2003b
; Lanius et al., 2003B
], or a counting Stroop task using combat words [Shin et al., 2001
]. Similarly, studies using resting paradigms [Bremner et al., 1997
], symptom provocation [Driessen et al., 2004
; Lanius et al., 2001
] and active memory tasks also found OFC dysfunction. Studies using SPECT to measure benzodiazepine receptor binding affinity have found both reductions [Bremner et al., 2000
] and unchanged [Fujita et al., 2004
] binding in the mPFC of war veterans. The latter finding was related to Gulf War veterans, whereas the former included veterans from the Vietnam era. An alteration in benzodiazepine receptors is thought to be involved in causing PTSD symptoms such as elevated levels of anxiety.
Several studies have suggested a relationship or direct functional link between the amygdala and the mPFC regions discussed here. In fact, four functional imaging studies [Driessen et al., 2004
; Semple et al., 2000
; Shin et al., 2004a
] have found a decrease in mPFC activity and a simultaneous hyperactivation of the amygdala simultaneously in patients with PTSD. It is thought that the mPFC provides a system of negative feedback to the amygdala, regulating its activation during emotional and fearful conditions: An increase in mPFC activity inhibits activation of the amygdala, whereas a decrease in mPFC activity, as found in numerous imaging studies in PTSD, seems to be connected to increased, or unchecked, amygdalar activity.
Although there is significant agreement about the connection of mPFC and amygdalar activity among the functional imaging studies, some findings point in different directions. Gilboa et al. 
reported a parallel increase in mPFC and amygdalar activity, for example. Conversely, another study reported parallel hypoactivation of these structures in a group of combat veterans with PTSD [Liberzon et al., 2003
]. Other PTSD studies report no changes in amygdalar [Bremner et al., 1999a
; Britton et al., 2005
; Lanius et al., 2001
; Yang et al., 2004
] or mPFC [Bonne et al., 2005
; Semple et al., 1996
] activity. One possible explanation for the lack of amygdalar activation in two of these studies [Britton et al., 2005
; Lanius et al., 2001
] is the use of traumatic scripts (internally generated stimuli as opposed to externally generated sounds or images). Yang et al. 
attributed their lack of amygdalar activation to paradigm design and small sample size (n
= 11). The fact that Rauch et al. 
did not observe any mPFC changes is difficult to explain. In a more recent symptom provocation study using the presentation of emotional faces, activity in the mPFC was significantly reduced in patients with PTSD [Shin et al., 2005
]. Furthermore, studies using combat pictures [Bremner et al., 1999b
] and slides related to natural disaster [Yang et al., 2004
] found significantly reduced activation of the mPFC. One possibility for the lack of results in the study by Rauch et al. 
could be the presentation of masked emotional faces, a practice not employed by studies showing reduced mPFC activity. Semple et al. 
also failed to find a difference in mPFC activity, yet they did manage to do so in a more recent study using a similar auditory continuous performance task paradigm. Finally, Lanius et al. 
found an increase in mPFC/ACC region, as opposed to the decreased activation trend. A possible explanation for this is the exclusive participation of subjects with dissociative responses to fearful stimuli, as we discuss further on. In a SPECT study, Zubieta et al. 
also reported an increased mPFC activity and hypothesized hyperactive dysfunction of the mPFC.
Inconsistencies are far from uncommon in neuroimaging studies of PTSD. For instance, findings in the hippocampus and parahippocampus are highly inconsistent when considered both individually and compared to each other. The parahippocampal gyrus, a region anatomically adjacent to the hippocampus, is liaison for many neocortical projections from the hippocampus and also the source of most afferents to the hippocampus. Activity in these structures is therefore related and can be compared to a certain extent. Despite their functional relationship in one of the limbic pathways, results in functional imaging studies of PTSD appear to be altered regarding these regions, because the majority of findings suggest a decrease in hippocampal functioning alongside increased parahippocampal activity. When we look at these results more closely, however, it is possible to find trends of neural activity disruption in PTSD.
The hippocampus plays a critical role in the consolidation of novel memories of facts and events. Several studies have shown that patients with chronic PTSD perform significantly more poorly on hippocampal-based memory and learning tasks [Bremner et al., 1993
]. Starting from this premise, a multitude of studies have explored the hippocampal structure of patients with PTSD. A review by Geuze et al. 
summarized the 14 MRI-based hippocampal volume reduction studies in PTSD as being inconsistent, because both reductions and insignificant differences were observed. Studies reporting differences in the functional properties of the hippocampus have similarly presented consistency issues. Altered hippocampal function was reported mostly in paradigms that employ memory to elicit hippocampal activity. PET studies by Bremner et al. using declarative memory tasks [Bremner et al., 2003a
] and script-driven imagery [Bremner et al., 1999a
] have shown a failure or reduced activation of the hippocampus. In addition, Shin et al. [2004b]
demonstrated reduced hippocampal activation using PET during a word-stem completion task. On the contrary, in the only known fMRI study to report hippocampal dysfunction, Shin et al. 
found increased hippocampal activity during a counting Stroop task that uses emotionally valenced words. Finally, using a resting paradigm, Bremner et al. 
observed reduced hippocampal functioning when administering the α2
receptor-antagonist yohimbine. In conclusion, reduced activation of the hippocampus is found in patients with PTSD during memory-related tasks, whereas studies using tasks with emotional content report inconsistent findings.
The parahippocampal gyrus is to a great extent functionally related to the hippocampus. The majority of findings related to this structure show a trend of increased activity, which could contradict the theory of memory deficits in PTSD. The parahippocampus is an extensive neural structure with a large functional diversity. In analyzing the studies that specified the precise location of altered parahippocampal functioning, we can attempt to derive several interesting conclusions. The studies that suggest decreased parahippocampal functioning [Lanius et al., 2002
] refer to more specific regions such as the entorhinal and perirhinal cortices (Brodmann’s areas 28 and 35, respectively). The entorhinal cortex has been found to be one of the major afferents to the hippocampus. Results for these specific regions reported a decrease in activity in patients with PTSD. Both regions are found to be functionally related to emotion, memory, and association of these memories. Another region, anatomically different but functionally similar to these areas, the retrosplenial cortex, is situated in the posterior cingulate cortex (Brodmann’s area 30). This region is also involved as an intermediary between the hippocampus and more cortical areas, and findings from the same studies show reduced activation in patients with PTSD.
On the other hand, three studies that reported increases in parahippocampal activity referred more specifically to the more posterior-oriented lingual gyrus [Brodmann’s area 19; Bremner et al., 1999a
; Shin et al., 2001
; Yang et al., 2004
]. This specific region has previously been linked to visuospatial processing and visual association. A possible explanation for the increased activity of this area, and perhaps other regions of the parahippocampus, is that it may facilitate or trigger flashbacks and intrusive thoughts. The fact that some studies report the specific areas within a region of interest enables us to make the distinctions found above. Other studies unfortunately did not report their results in great detail, making it difficult to trace the trend within the parahippocampus. It is therefore important to note that a future direction in the field of neuroimaging should be a common way of reporting results, paying close attention to the level of detail. This includes a more specific categorization of parahippocampal structures and a better understanding of the role these play in various networks.
A less documented finding in functional neuroimaging studies is the involvement of the thalamus in patients with PTSD. The thalamus is an important relay station for the transmission of external sensory information to different areas of the cerebral cortex and limbic system, where this information is processed. Target regions include the frontal cortex, cingulate gyrus, amygdala, and hippocampus, all of which are closely related to the neural networks hypothesized to be active in PTSD. Two studies by Lanius et al. [2001
using traumatic script-driven imagery and another using traumatic memory recall [Lanius et al., 2003b
] report decreased thalamic activity. The disruption in thalamic activity could lead to several of the traits displayed by the clinical presentation of PTSD. Due to its functional nature, a disruption in activity of the thalamus could lead to the misinterpretation of external stimuli. It is important to note, however, that the only research group that found altered activity in PTSD with regard to the thalamus, used fMRI as opposed to SPECT or PET. Furthermore, this particular group uses a 4 Tesla MRI scanner as opposed to the more conventional (and lower resolution) 1.5 and 3 Tesla scanners. Due to the importance of the thalamus in relaying sensory information to higher cortical regions, it is a region of interest in PTSD research that deserves and requires further investigation.
Summarizing and finding trends in the results of the functional imaging studies to date remain a complicated issue. One possible explanation underlying discrepancies among the various studies lies in the actual design of the paradigms used to measure neural activity in patients with PTSD. According to our current research, 45 studies published used functional neuroimaging techniques in PTSD research. These studies make use of a wide range of methodologies: measuring resting brain activity, presenting a wide range of stimuli, and using active tasks performed by a subject. Within these main groupings there are further distinctions to be made, such as the type of stimulus (auditory, visual, trauma script, personal script), type of task (active recall, counting Stroop task, auditory continuous performance task), and type of tracer used in PET or SPECT studies. Due to this variation, difficulties arise when comparing data across different studies.
Another issue that confounds comparison is a wide array of subjects in specific studies and when comparing different studies, including patients with a broad trauma spectrum and of different sexes. It is important to distinguish between trauma types, such as trauma caused by MVAs, sexual assault, combat situations, natural disasters, and so forth. This could be one reason behind the inconsistency in hippocampal activation. Furthermore, studies have shown significant differences in properties between the male and female brain [Goldstein et al., 2001
]. PTSD is a complex anxiety disorder with foundations in an extensive neural circuitry. By examining patients with a common traumatic history and sex it is possible to analyze neural activity with higher precision, and potential differences between the groups can be brought to light.
In addition to the different traumas that cause the onset of PTSD, the clinical presentation of symptoms also varies between patients. Recently, it has been hypothesized that there are two main categories of PTSD symptoms, closely related to the criteria that make up the disorder. Whereas some patients tend to be hyperaroused, others show numbing in response to fearful situations. This latter often have moments of dissociation, as opposed to the former, who tend to be hypervigilant and experience flashbacks of their trauma. In a study performed by Lanius et al. 
, functional connectivity was measured using fMRI in both dissociated and flashback PTSD groups. The findings indicate a different neural connectivity between the two groups, with the dissociated group showing greater connectivity in the left inferior frontal gyrus, an area previously found to be related to the determination of self-relevance of emotional statements [Lanius et al., 2005
]. Moreover, in a case report of a married couple involved in an MVA, Lanius et al. [2003a]
clearly presented a case for different types of PTSD. The husband responded to a traumatic script about the accident in a state of hyperarousal, whereas his wife became numb and frozen. Because there is a possible difference in brain activation patterns between the flashback and dissociated PTSD groups, comparing these two groups of patients may lead to distortions in the outcome of a study.
An interesting observation can also be drawn from the discrepancy in abnormalities between functional versus structural neuroimaging. Although functional neuroimaging demonstrates abnormalities in the mPFC (including ACC) and amygdalar circuit, structural MRI studies have exclusively focused on the hippocampus, but not on the amygdala. Functional neuroimaging studies suggest that there are clear differences in metabolic acticity in the mPFC–amygdala circuit; therefore, it would be interesting to investigate further whether patients with PTSD show structural differences with respect to their amygdalae.
Another important issue that needs to be raised is that one may wonder whether the abnormalities found in functional neuroimaging studies are specific to PTSD. Similar findings have also been reported in other studies, targeting other anxiety disorders, such as obsessive–compulsive disorder [Nakao et al., 2005
], panic disorder [van den Heuvel et al., 2005
], and generalized social phobia [Phan et al., 2005]. We must be careful, however, in assuming similarity with these other anxiety disorders due to the specificity of the experimental designs. Studies that target patients with PTSD use different experimental designs, with content specific to the disorder. For example, script-driven imagery for patients with PTSD differs from that used for patients with other anxiety disorders. In turn, this may elicit different, disease-specific brain activation patterns.