What parts of the brain are involved in posttraumatic disorder? A recent study of Vietnam veterans used a novel and clever strategy to produce some unexpected results.

Recent developments in brain imaging have allowed scientists to study the brains of patients afflicted with a variety of disorders. Identifying the parts of the brain that are involved in those disorders is key to understanding how the disorders arise and are maintained.

Brain imaging studies of posttraumatic stress disorder ( ) have identified a few key brain regions whose function appears to be altered in PTSD, most notably the amygdala, the ventromedial prefrontal cortex (vmPFC) and the hippocampus.

The amygdala is an almond-shaped region ("amygdala" is greek for almond) that is key to the normal expression of emotions, especially . Brain imaging studies see high activity in the amygdala when subjects experience , stress or phobias.

The vmPFC can be thought of as a "higher" or "more sophisticated" part of the brain, involved in less well defined activities such as "emotional processing" and " ".

The hippocampus is a large region that is, very simply, involved in , especially spatial memory (such as for, and of, places)

A very generalised model of what happens during normal responses to anxiety is this; a person enounters some environmental cue that signals danger, for example, they see a tiger. This information is sent to the amygdala, which gets fired up and starts sending out "fight or flight" responses to other parts of the brain. However, the vmPFC, being involved in "higher thinking", has a quiet word with the amygdala, saying "look, the tiger is in a cage, you know what a cage is, tigers can't escape from cages, it's OK, calm down". Another part of the brain, the hippocampus, helps out, providing information about the context of the event (we're at a zoo, we know what zoo's look like, we've seen them before). In summary, the vmPFC inhibits the amygdala to keep fearful responses in check.

Brain imaging studies of PTSD sufferers generally show two things; reduced activity in the vmPFC and increased activity in the amygdala. A long-held interpretation of these studies is that, in PTSD, the vmPFC is asleep at the wheel, allowing the amygdala to go unchecked and thus produce many of the intense anxiety symptoms that are a key feature of PTSD.

What these studies don't tell us tho', is how this imbalance comes about; does having reduced vmPFC function lead to PTSD, or does having PTSD shut down the vmPFC? To address these issues would require shutting down or damaging the vmPFC and looking for the development of PTSD, obviously not an experiment that can or should be performed with people. However, Michael Koenigs, Jordan Grafman and colleagues at the NIH came up with a very elegant way of answering these questions.

Grafman is one of the scientists behind the Vietnam Study (VHIS). This study is a 30 year analysis of Vietnam veterans that measures a whole host of outcomes. Among the myriad of unfortunate effects of combat on soliders, two things occur frequently; brain injury and, especially in Vietnam, PTSD. The VHIS analyzed 245 Vietnam combat veterans, of whom 193 had some permanent brain damage. The remaining 52 had experienced combat but not suffered lasting brain damage. As part of the VHIS, the location and extent of brain damage was determined in each subject using brain imaging. Koenigs and colleagues then asked a simple question of each veteran; have you ever experienced PTSD? Around 45% had. They then grouped patients into PTSD+ and PTSD- groups based upon their responses and re-analyzed the results from the brain scans to see if damage to particular parts of the brain correlated with the occurrence of PTSD.

What they found was startling; patients who had damage to the vmPFC and amygdala were much LESS likely to have developed PTSD. For the amygdala, this makes sense, but for the vmPFC, this was the complete opposite of what would be predicted from previous studies. Also noteworthy; hippocampal damage was not associated with an increase or decrease in PTSD symptoms.

To be sure of this conclusion, Koenigs and co flipped their analysis; they classified their patients into those who had damage of the vmPFC or amygdala and then looked to see if there was an increased incidence of PTSD. There was. In fact, of those with amygdala damage, none had ever experienced PTSD symptoms. The reduction in PTSD presented as an overall reduction in the intensity of all symptoms rather than a complete absence of PTSD or a reduction in a subset of symptoms. It's important to make clear that the injury that caused the brain damage is not necessarily the event that caused the patients to develop PTSD; the brain damage here is just being used as an anatomical indicator of what parts of the brain are important for developing PTSD

The most obvious interpretation is that persons with damage to these areas are protected from the development of PTSD, which could be interpreted as good. However, this protection comes at a significant cost. Damage to these areas is associated with other cognitive problems, most notably in emotional processing and decision making.

From a scientific perspective, these findings require a reassessment of how we think PTSD develops, most notably, how do the findings with the Koenig study fit with studies showing that PTSD sufferers have reduced activity in their vmPFC?

As always, the devil may be in the detail. Perhaps the conversation between vmPFC and amygdala is not all one way; perhaps the amygdala talks back. Or perhaps the vmPFC opens multiple lines of communication with the amygdala and not all are inactive during PTSD. Maybe even having most of those lines shut down allows others to be heard more clearly. Evidence from animal studies points to these answers. Other brain regions are almost certainly involved and these may influence the activity of the vmPFC or amygdala. Or the amygdala and vmPFC may be required for the storage and processing of traumatic memories, or the reactivation of those memories in response to reminders in . Again, basic science studies indicates that this may be the case, but only now do these studies make sense in terms of the clinical picture.

Whatever the final answer, these studies show the importance of addressing human disorders with a basic science approach. Brain imaging studies can only show a snapshot of the current situation; experimental manipulations are obviously very difficult to do; one cannot just shut down a patients vmPFC and then see if they develop PTSD. In this paper, Koenig and Grafman's clever use of the Vietnam Head Injury Study allowed them to ask a question that would otherwise have been difficult to answer, and has provided vital new information for the development of treatments to combat PTSD.

The full version of the paper appeared in Nature Neuroscience in February 2008.

Image credit; Molecular Psychiatry 2008 Mar;13(3):313-24