Functional neuroimaging studies have been performed to map out the neural circuitry of PTSD [172
]. These studies are consistent with dysfunction in a network of related brain areas including medial prefrontal cortex and hippocampus. We measured brain blood flow with PET and [15
O during exposure to personalized scripts of childhood sexual abuse. Twenty two women with a history of childhood sexual abuse underwent injection of H2
O] followed by positron emission tomography (PET) imaging of the brain while listening to neutral and traumatic (personalized childhood sexual abuse events) scripts. Brain blood flow during exposure to traumatic versus neutral scripts was compared between sexually abused women with and without PTSD. Memories of childhood sexual abuse were associated with greater increases in blood flow in portions of anterior prefrontal cortex (superior and middle frontal gyri-Areas 6 and 9), posterior cingulate (area 31), and motor cortex in sexually abused women with PTSD compared to sexually abused women without PTSD. Abuse memories were associated with alterations in blood flow in medial prefrontal cortex, with decreased blood flow in subcallosal gyrus-area 25, and a failure of activation in anterior cingulate-area 32. There was also decreased blood flow in right hippocampus, fusiform/inferior temporal gyrus, supra-marginal gyrus, and visual association cortex in PTSD relative to non-PTSD women [174
]. This study replicated findings of decreased function in medial prefrontal cortex and increased function in posterior cingulate in combat-related PTSD during exposure to combat-related slides and sounds [175
]. In another study 8 women with childhood sexual abuse and PTSD were compared to 8 women with abuse without PTSD using PET during exposure to script-driven imagery of childhood abuse. The authors found increases in orbitofrontal cortex and anterior temporal pole in both groups of subjects, with greater increases in these areas in the PTSD group. PTSD patients showed a relative failure of anterior cingulate/medial pre-frontal cortex activation compared to controls. The PTSD patients (but not controls) showed decreased blood flow in anteromedial portions of prefrontal cortex and left inferior frontal gyrus [176
]. Several other studies have shown a failure of medial prefrontal cortical activation in PTSD related to other traumas including combat [58
These studies have relied on specific traumatic cues to activate personalized traumatic memories and PTSD symptoms in patients with PTSD. Another method to probe neural circuits in PTSD is to assess neural correlates of retrieval of emotionally valenced declarative memory. In this type of paradigm, instead of using a traditional declarative memory task, such as retrieval of word pairs like “gold-west”, which has been the standard of memory research for several decades, words with emotional valence, such as “stench-fear” are utilized [185
]. Although there has been relatively little research on retrieval of emotionally valenced words, it is of interest from the standpoint of PTSD as a method for activating neural pathways relevant to trauma and memory. If PTSD patients demonstrate a pattern of brain activation during retrieval of emotionally valenced declarative memory that is similar to that seen during exposure to other tasks that stimulate brain networks mediating PTSD symptoms, such as exposure to personalized scripts of childhood trauma, or exposure to trauma-related pictures and sounds, then that would provide convergent evidence for dysfunction of a specific neural circuit in the processing of emotional memory in PTSD. We recently used PET in the examination of neural correlates of retrieval of emotionally valenced declarative memory in 10 women with a history of childhood sexual abuse and the diagnosis of PTSD and 11 women without abuse or PTSD. We hypothesized that retrieval of emotionally valenced words would result in an altered pattern of brain activation in patients with PTSD similar to that seen in prior studies of exposure to cues of personalized traumatic memories. Specifically we hypothesized that retrieval of emotionally valenced words in PTSD patients relative to non-PTSD would result in decreased blood flow in medial prefrontal cortex (subcallosal gyrus and other parts of anterior cingulate), hippocampus, and fusiform gyrus/inferior temporal cortex (), with increased blood flow in posterior cingulate, motor and parietal cortex, and dorsolateral prefrontal cortex. PTSD patients during retrieval of emotionally valenced word pairs showed greater decreases in blood flow in an extensive area which included orbitofrontal cortex, anterior cingulate, and medial prefrontal cortex (Brodmann’s areas 25, 32, 9), left hippocampus, and fusiform gyrus/inferior temporal gyrus, with increased activation in posterior cingulate, left inferior parietal cortex, left middle frontal gyrus, and visual association and motor cortex. There were no differences in patterns of brain activation during retrieval of neutral word pairs between patients and controls. These findings were similar to prior imaging studies in PTSD from our group using trauma-specific stimuli for symptom provocation, adding further supportive evidence for a dysfunctional network of brain areas involved in memory, including hippocampus, medial prefrontal cortex and cingulate, in PTSD [180
Another study examined neural correlates of the Stroop task in sexually abused women with PTSD. The Stroop task involves color naming semantically incongruent words (e.g., name the color of the word green printed in the color red). The Stroop task has been consistently found to be associated with activation of the anterior cingulate in normal subjects, an effect attributed to the divided attention or inhibition of responses involved in the task. Emotional Stroop tasks (e.g. name the color of a trauma specific word like rape) in abused women with PTSD have also been shown to be associated with a delay in color naming in PTSD [155
]. Women with early childhood sexual abuse-related PTSD (n=12) and women with abuse but without PTSD (n=9) underwent positron emission tomographic measurement of cerebral blood flow during exposure to control, color Stroop, and emotional Stroop conditions. Women with abuse with PTSD (but not abused non-PTSD women) had a relative decrease in anterior cingulate blood flow during exposure to the emotional (but not color) classic Stroop task. During the color Stroop there were also relatively greater increases in blood flow in non-PTSD compared with PTSD women in right visual association cortex, cuneus, and right inferior parietal lobule. These findings were consistent with dysfunction of the anterior cingulate/medial prefrontal cortex in women with early abuse-related PTSD [186
We compared hippocampal function and structure in 33 women with and without early childhood sexual abuse and PTSD. Women with abuse with and without PTSD were studied during encoding of a verbal memory paragraph compared to a control in conjunction with measurement of brain blood flow with PET. Subjects underwent four PET scans using methods described by us previously in detail [174
] in conjunction with encoding of a control task and an active paragraph encoding. There were no differences in blood flow during the control task between groups, however there were significantly greater increases in blood flow during verbal memory encoding in the hippocampus in non-PTSD abused women relative to PTSD women (F=14.93; df 1,20; p<0.001). PTSD women also had smaller left hippocampal volume on MRI volumetrics compared to abused women without PTSD and non-abused non-PTSD women. Differences in hippocampal activation were statistically significant after covarying for left hippocampal volume, suggesting that failure of activation was not secondary to smaller hippocampal volume in patients with PTSD. There was a significant relationship between increased dissociative states as measured with the Clinician-Administered Dissociative States Scale (CADSS) and smaller left hippocampal volume as measured with MRI in abused women as measured with logistic regression (R Squared=0.30, F=3.90; df=1; p<.05) [116
]. Another study in men and women with Vietnam service and PTSD found a failure of hippocampal activation with a word stem completion memory task [126
In addition to a failure of hippocampal activation with cognitive tasks, studies found decreased hippocampal activation with symptom provocation in PTSD. Studies have found decreased hippocampal function during traumatic remembrance stimulated with trauma-specific scripts [174
], stimulation of PTSD symptoms with yohimbine [58
], or during recall of emotionally negative words in PTSD [180
], although increased function was seen during counting of combat words [182
]. Increased dissociation and flashbacks during these tasks may lead to (or be caused by) decreased hippocampal function, leading to the divergence from normal declarative memories that can often occur in these states [136
Although some studies have demonstrated increased amygdala function in PTSD [187
], the experience to date suggests that increased amygdala involvement is not necessarily seen in all of the study paradigms applied to PTSD. While some studies found amygdala activation with trauma-specific stimuli [188
] a larger number did not [58
]. It is more likely that specific tasks are required to show increased amygdala function in PTSD. For instance, Rauch et al
. found that exposure to masked fearful faces was associated with greater amygdala activation in PTSD [189
], and we found increased amygdala activation during acquisition of fear in a classical fear conditioning paradigm (Bremner et al
in press). In summary, increased amygdala function has not been shown to be non-specifically associated with traumatic remembrance in PTSD, however there are suggestions that alterations in amygdala activity do play a role in PTSD, probably related to specific mechanisms of the disorder. Future studies are required in this area.
Imaging studies that involved provocation of PTSD symptoms in adults with PTSD are also consistent with dysfunction in medial prefrontal cortex/anterior cingulate [190
]. In an earlier study PTSD symptoms were stimulated through activation of the brain norepinephrine system yohimbine (an alpha-2 noradrenergic receptor antagonist which stimulates norepinephrine release in the brain) in conjunction with PET imaging of brain metabolism with FDG. PTSD patients showed decreased function in orbitofrontal cortex, relative to controls [58
]. Decreased baseline blood flow during an attentional task was seen in medial prefrontal cortex in patients with PTSD and substance abuse [187
]. Other studies showed dysfunction in various subregions of medial prefrontal cortex/anterior cingulate (Areas 32, 24, and 25), including a failure of activation and decreased function relative to controls during exposure to traumatic scripts [174
], combat-related slides and/or sounds [175
] a trauma-specific counting Stroop task [182
] and an emotional Stroop task [186
]. In the other parts of medial prefrontal cortex (orbitofrontal cortex (Area 11), Area 9 and 10), the findings have been mixed [183
], with about an equal number of studies showing increases as decreases. In conclusion, it is reasonable to postulate that exposure to standard materials such as traumatic scripts and slides is associated with a relative failure of function in the “extended anterior cingulate” portion of medial prefrontal cortex (Areas 24, 32, 25), however more studies are required to confirm this finding.
Studies have begun to use neuroimaging to examine central receptor function in PTSD. Animal studies showed that chronic stress leads to a decrease in benzodiazepine receptor binding in frontal cortex. We used SPECT with [123
I]Iomazenil to quantitate benzodiazepine receptor binding in patients with combat-related PTSD and healthy controls. In this study we found a decrease in benzodiazepine receptor binding in medial prefrontal cortex (Brodmann’s area 9) in 13 patients with combat-related PTSD compared to 13 case-matched healthy controls [193
]. These findings were consistent with animal studies of stress showing decreased binding in frontal lobe.
Functionally, the cingulate has been divided into an anterior portion involved in emotion and selection for action, and a posterior portion involved in visuospatial processing [97
]. Recent imaging studies in humans, however, have been consistent with a role for the posterior cingulate in processing of emotional and traumatic material in normal individuals [194
]. Multiple PET studies found increased posterior cingulate function during stimulation of traumatic memories in PTSD [174
]. These findings corroborate the inclusion of the entire cingulate in the original limbic model.
The dorsolateral prefrontal cortex, which includes areas such as middle and inferior frontal gyri, is involved in cognitive functions, language and speech [196
]. Prefrontal cortex plays an important role in the activation of memory pathways and sustained attention that are elicited during the stress response. This area has functional connections with other regions mediating cognitive and emotional responses to stress, including motor cortex, parietal cortex, cingulate, hippocampus and amygdala. Disruption of circuits between the dorsolateral prefrontal cortex and other regions involved in emotion and the stress response (e.g. limbic regions) may lead to disconnection between cognitive and emotional processing and responses to traumatic events.
There have in fact been several studies showing altered function in dorsolateral prefrontal cortex with PTSD symptom provocation. Studies found decreased function in either inferior or middle frontal gyri [58
]. Dysfunction in this area may be involved in the dysfunction of memory, speech and cognition seen in PTSD patients, especially during periods of stress or traumatic reminders. A functional disconnection between “higher” prefrontal cortical areas involved in abstract thought, language and cognition and “lower” limbic areas that govern primary emotions may underlie unregulated emotions, traumatic dissociative memory recall in PTSD, and difficulties in verbalization of traumatic experiences.
The parietal cortex plays a critical role in visuospatial processing that is involved in the response to threat [197
]. Two or more studies have found decreased function with traumatic remembrance in visual association cortex [174
], while increases and decreases were seen in the precuneus (which plays a role in processing of visual memory). Several studies found decreased function in parietal cortex [58
] with a smaller number of studies showing an increase [174
]. These studies are consistent with alterations in parietal and visual association cortical function in PTSD, probably mediating alterations in cognitive functions associated with these areas.