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Damaged Brain Regions Protect Against PTSD

ARTICLE IN BRIEF

  • ✓ Vietnam veterans with damage in the amygdala and ventromedial prefrontal cortex areas were much less likely to develop post-traumatic stress disorder than those with no brain damage or with lesions elsewhere in the brain.

A CT study of brain lesions in Vietnam War combat veterans found that damage to either the amygdala or ventromedial prefrontal cortex protects against post-traumatic stress disorder (PTSD).

Veterans with damage in those areas were much less likely to develop PTSD than those with no brain damage or with lesions elsewhere in the brain, reported Michael Koenigs, PhD, a postdoctoral fellow at the NINDS Cognitive Neuroscience Section, and colleagues in a paper published online Dec. 23 in the journal Nature Neuroscience.

None of the 15 veterans with amygdala lesions were ever diagnosed with PTSD, but 18 percent of the 40 subjects with damage to the ventromedial prefrontal cortex developed PTSD. In contrast, 40 percent of the 133 veterans with damage in non-ventromedial prefrontal cortex or other non-amygdala regions developed PTSD, as did 48 percent of 52 vets with no evident brain damage.

The decreased prevalence of PTSD was attributed to less intense symptoms rather than complete lack of symptoms, the authors said.

In contrast, posterior lesions did not protect against PTSD. Forty- to 45-percent of those with posterior lesions did have PTSD manifestations at some time.

Whether or not the hippocampus was damaged had no effect on the prevalence of PTSD, challenging a long-held emphasis on the importance of the hippocampus in PTSD.

EVIDENCE FOR BRAIN REGION INVOLVEMENT

Commenting on the paper, Maurizio Corbetta, MD, Head of Stroke and Brain Injury Rehabilitation at Washington University in St. Louis, told Neurology Today: “The lesion analysis provides direct evidence for the causal role of these regions in the pathophysiology of PTSD.”

Earlier studies have suggested the importance of these two regions in PTSD. But with the new data, “what we're saying is that they're not only important, but they're also critical to the development of PTSD,” senior investigator of the study, Jordan Grafman, PhD, chief of the NINDS Cognitive Neuroscience Section, told Neurology Today.

Figure

A healthy adult brain is shown on the left. MRIs of brains from the veterans are on the right. Investigators analyzed and compared the distribution of lesions in those who developed PTSD and those who did not. The darker blue and green regions show areas where damage was associated with a small likelihood of developing PTSD: a bilateral frontal region and a bilateral anterior temporal region. The colors correspond to a values chart below: those with higher negative values (the darker blue and green areas) indicate areas where damage was infrequently associated with PTSD; the positive values (0–6) correspond to areas where there was a higher likelihood of developing PTSD. In the temporal lobe, the density of voxels with negative values was much greater in anterior areas, which contained the amygdala.The analysis suggests that the ventral medial prefrontal cortex and amygdala may be critical neural substrates for the development of PTSD.

Dr. Grafman also acknowledged the paradoxical findings. “Usually when somebody has a brain injury, we think they're going to do worse in everything. They're certainly not going to get better,” he said. “These patients will have their own characteristic deficits, because of where their lesions are. But paradoxically, this is one aspect of functioning that actually benefits from the lesion.”

The 193 subjects with brain damage in this study were drawn from the W.E. Caveness Vietnam Head Injury Study (VHIS) registry of 1,221 American soldiers, who had penetrating head injuries suffered in Vietnam. They were initially enrolled in the registry from 1967 to 1970.

The 52 non-head-injured soldiers were recruited from Veterans Administration records of non-head-injured veterans who had combat exposure in Vietnam during the same years and were in the same age range as soldiers in the Caveness registry.

Researchers analyzed the brain lesions using CT without contrast at the Bethesda Naval Hospital. Additionally, each of the 245 participants in the study was evaluated for PTSD using the Structured Clinical Interview for DSM-IV-TR Axis I disorders for non-patients. A psychiatrist trained to administer the evaluation performed the assessment between 2003 and 2006. Veterans were classified as having PTSD at some time in a lifetime or never having PTSD.

The Vietnam veterans chosen for this PTSD study all had penetrating head injuries, while soldiers from more current conflicts are more likely to suffer from blast injuries with intact skull, Dr. Grafman said.

CT VERSUS MRI

Some researchers have suggested that MRI would have been a more precise way of localizing the lesions.

“MRI may have allowed a higher degree of spatial resolution for the anatomical localization especially when separating adjacent structures such as the hippocampus and amygdala,” Dr. Corbetta said, adding that the separation between the two areas is not that easy with CT.

“However, the results in my opinion are not dependent on the specific type of scan. Physiological scans like PET or fMRI might have provided additional information, especially in picking up distant effects of the lesions onto anatomically normal brain circuits.”

Dr. Grafman noted that most of the soldiers they evaluated have metal fragments in the brain, either from combat or from surgery, making MRI too risky.

POST-TRAUMATIC AMNESIA

Soldiers with amygdala and ventromedial prefrontal cortex lesions who did not have PTSD had good memories as judged objectively by performance on the Wechsler Memory Scale, a standard clinical test of memory, Dr. Grafman said. In addition, he said, the researchers videotaped participants talking about their experiences in Vietnam; those with amygdala or ventromedial prefrontal cortex lesions had no difficulty recalling traumatic memories from Vietnam.

Figure

The color indicates the number of veterans (40) who had substantial damage to the ventral medial prefrontal cortex (vmPFC) in either region.Pictured (top row) are sagittal views of the of those with substantial damage to the vmPFC in either region; (middle row) coronal views of a healthy adult brain; (bottom row) coronal views of the those with lesions in the ventral medial prefrontal cortex. Of the 40 vmPFC patients, 14 had bilateral vmPFC lesions, 15 had exclusively or (bottom row) predominantly left vmPFC lesions and 11 had exclusively or predominantly right vmPFC lesions. Of the seven vmPFC patients who developed PTSD, two had bilateral vmPFC lesions, two had exclusively or predominantly left vmPFC lesions and three had exclusively or predominantly right vmPFC lesions. vmPFC lesions typically originated in the polar aspect of frontal lobe.

The protective effect of the lesions lasted a lifetime, even when veterans recalled traumatic events. They might have feelings about those events, but would not suffer the dysfunction of those who had PTSD, Dr. Grafman said.

THERAPEUTIC TARGETS

The new findings give further support to the development of therapies that target the amygdala and ventromedial prefrontal cortex, Dr. Grafman and others said.

“This might even lead to the development of inactivation strategies — transcranial magnetic stimulation, deep brain stimulation, or even surgical approaches,” Israel Liberzon, MD, professor of psychiatry, psychology, and neuroscience, and associate chair of psychiatry at the University of Michigan, told Neurology Today.

“Since our effects occurred in either hemisphere, you wouldn't have to do bilateral treatments to reduce the intensity of PTSD,” Dr. Grafman said.

Behavioral therapies that help people put events in the past into context and help people manage emotions also could play a role, he said.

UNANSWERED QUESTIONS

Meanwhile, the study did not attempt to determine the effect of persistent PTSD on brain structures and it was not intended to address underlying mechanisms.

“The evidence that lesions in the amygdala and ventromedial prefrontal cortex are associated with a lower incidence of PTSD does not say anything about the underlying physiological mechanism because CT does not measure function,” Dr. Corbetta said. “These results are consistent with a hypothesis of amygdala hyperactivity, but do not directly test that hypothesis.”

What also remains unknown is where the pattern of neural activity supporting PTSD arises in the network of regions connected with the amygdala and ventromedial prefrontal cortex, he said, noting that brain regions do not work in isolation.

“These focal lesions may have a more distributed effect on the networks to which these brain regions are connected,” Dr. Corbetta said.

The authors call for further research to specify the nature of the interaction between the ventromedial prefrontal cortex and amygdala and how dysfunction in this circuit contributes to PTSD. Specifically, they suggest research to address the effect of damage to the pathway between the two brain structures — for example, the uncinate fasciculus — on emotional processing.

REFERENCES

• Koenigs M, Huey ED, Grafman J, et al. Focal brain damage protects against post-traumatic stress disorder in combat veterans. Nat Neurosci 2007; E-pub 2007 Dec. 23.
    • The W.E. Caveness Vietnam Head Injury Study: www.bethesda.med.navy.mil/Professional/Research/Vietnam_Head_Injury.aspx.