Biomarker For PTSD And Why PTSD Is So Difficult To Treat

"PTSD can be a debilitating disorder that creates cognitive disability as well as internal stress for the victim and produces stress for family and friends. And it is an increasing public health concern," says Bruce McEwen, PhD, of Rockefeller University in New York City. "Understanding what goes on in the brain is critical to finding successful treatments, including pharmaceutical therapies and cognitive behavioral therapies that enhance extinction of the fear-related memories."

PTSD is the most common mental health disorder among veterans of the conflicts in Afghanistan and Iraq. As the profile of PTSD rises, new findings are increasing researchers' understanding of the way memory malfunctions in PTSD, creating characteristic symptoms such as flashbacks and fear reactions to trigger sounds, even in safe situations.

The disorder is characterized by flashbacks, emotional numbness, and insomnia. It can result from a catastrophic and threatening event -- a natural disaster, wartime situation, accident, domestic abuse, or violent crime. Symptoms usually develop within three months, but can emerge years after the initial trauma. Estimates indicate more than 7.5 million American adults have the disorder, according to the National Institute of Mental Health.

New research with veterans from the Serbo-Croatian War of the early 1990s confirms previous research showing that veterans with PTSD react in fear even when shown signals they have come to associate with safety. It also has led to the identification of the first biomarker for PTSD, which may become useful in testing the value of treatments for the disorder.

"One of the central features of the disorder is the inability of the brain to distinguish between dangerous and safe situations," says Michael Davis, PhD, of Emory University School of Medicine. "For example, a woman who was raped by a stranger may later not even feel safe with her husband. That is, she has lost the ability to distinguish between dangerous and safe situations." Davis will be presenting a special lecture at Neuroscience 2007 titled "Neural Mechanisms of Fear Extinction: Implications for Psychotherapy."

Working with 33 veterans, Davis measured the degree to which subjects were startled, as well as their ability to overcome this fear response, as he evoked certain conditioned responses. He was assisted by Erica Duncan, MD, and Tanja Jovanovic, PhD, in this research. The study used yellow, green, and blue lights, which, in pairs, signaled caution or safety. Davis first trained the subjects to associate the yellow and green lights with a blast of air to the throat. How hard the veterans blinked was recorded as a measure of their startle response to this combination of colored lights. The study then created an association between a blue-green pairing of lights and no air blast, establishing a signal for relative safety.

To measure how safe the blue light made the subjects feel, Davis then recorded responses to a blue-yellow signal. What he found was that although healthy subjects startled less when they saw the blue and yellow lights than when they saw the green-yellow combination, those with PTSD could not suppress their fear response. This indicated an inability to respond to indicators of safety.

"This test can provide a more objective way of measuring fear control mechanisms that work in healthy people and do not work in patients with PTSD," says Davis. "In fact, this finding may provide one of the first biomarkers for PTSD, namely an objective physiological measure of abnormal fear regulation. It may also become a valuable clinical tool to assess and compare the effectiveness of different treatments in different populations of PTSD patients, such as civilians and combat veterans."

Researchers also are moving closer to an answer to the question of what causes combat-related PTSD, which develops in an estimated 12 percent of veterans returning from the current conflicts in Afghanistan and Iraq. A recent study reveals how a combat event can impair subsequent brain functioning. Although people with PTSD can temporarily learn to extinguish fear, they are unable to retain this ability.

Working with 14 pairs of identical twins from the Veterans Administration's Vietnam era twin registry, Mohammed Milad, PhD, at Boston's Massachusetts General Hospital and Harvard Medical School, developed a two-day fear conditioning protocol. In each pair of twins, only one had experienced combat; half of these veterans also had PTSD. On the first day, the subjects learned to associate a light with a mild shock. After several trials in which Milad displayed the light without administering the shock, he found that all groups of subjects were successful at disassociating the light from their fear of being shocked.

The following day, Milad recorded electrical resistance on the subjects' skin as a measure of their emotional response to the light. In contrast to the day before, subjects with PTSD showed a strong fear reaction to the light. Twins of the PTSD veterans as well as the other combat veterans and their twins all remained able to inhibit their fear.

"The inappropriate and long-lasting fear observed in PTSD has led investigators to hypothesize that PTSD patients are unable to inhibit or extinguish their conditioned fear responses," says Milad. "Our demonstration that extinction memory is deficient in PTSD veterans but intact in their noncombat co-twins suggests that the trauma itself caused this dysfunction.

"These findings argue against the possibility that the ability to control fear in PTSD patients had already been frail prior to the trauma due to genetic or environmental factors," he says. To further examine the biological basis for learning and extinguishing fear in the brain, Milad plans studies with twins using functional magnetic resonance imaging (fMRI).

More than just mechanisms for fear-related memory may go awry in the brains of people with PTSD, according to findings by Dutch researchers who show that learning unrelated to trauma also is affected.

"These neurobiological alterations witnessed in veterans with PTSD provide some acknowledgement that the problems experienced by them are not just figments of the imagination but very real neurobiological consequences of traumatic stress. It is this neurobiological war within that we should learn to wage and win," says Elbert Geuze, PhD, at the Military Mental Health Research Center in Utrecht, The Netherlands.

Using fMRI to monitor the brains of 24 male veterans, half with PTSD, Geuze zeroed in on the neural correlates of memory processing. The veterans in each group were matched so that pairs were approximately the same age, and had been deployed at the same time and to the same area.

Geuze first asked the veterans to memorize 12 pairs of words, which were neutral in terms of emotional content: stone and car, for example, or rose and house. Later, they were tested on their recall of the word pairs: Given "stone," they were asked to recall "car."

Compared with veterans without PTSD, those showing symptoms of the disorder had less activity in the frontal cortex and an overactive temporal cortex while learning and memorizing the word pairs. "Apparently patients are unable to fully recruit their frontal cortex, an area important for working memory processing," Geuze says.

When asked to recall the word pairs, they showed decreased activity in the brain's right frontal cortex, bilateral middle temporal gyri, and left hippocampus and parahippocampal gyrus. "Patients seem to use a wrong part of the brain-the superior temporal cortex instead of the medial temporal cortex, where the hippocampus is-to perform this task," he says. The frontal cortex, temporal cortex, and hippocampus all have critical roles in the basic cognitive processes of learning and memory. The hippocampus, for example, helps store newly created memories and is connected to areas of the brain responsible for thinking and language.

"These data support the long-held notion that altered activity in fronto-temporal circuits of the brain is related to deficits in memory performance in veterans with PTSD," Geuze says.

Another study examining learning among veterans with PTSD found that three different physical responses may all be responding to signals from the same areas of the brain, known to be involved in processing emotional material. Previous studies have shown these same areas of the brain areas are dysfunctional in PTSD.

A research team headed by D.A. Powell, PhD, of the Dorn Veterans Administration Medical Center in Columbia, S.C., worked with nearly 50 veterans, categorized in three groups: healthy veterans, with combat experience and without, and combat veterans with PTSD. The study involved a number of trials in which the subjects learned to associate a warning light and tone with a puff of air directed at their eyes. The warning signal was displayed five seconds before the tone, which sounded almost simultaneously with the puff of air.

When the PTSD combat veterans were shown the light after a few trials, Powell's research team found that the veterans' heart rate accelerated. The typical response to a sign of potential danger is for the heart to slow down. And this, in fact, is what the team found among both groups of veterans without PTSD.

It is also typical for subjects to blink in defense when their eyes are hit with a puff of air; this defensive eyeblink response is known to decrease over time, a process known as habituation. The researchers found that for PTSD veterans, the defensive eyeblink became habituated much faster than for the study's other subjects, in reaction both to the tone and to the actual puff of air.

"In other words, hyper-responsivity to a warning signal and hypo-responsivity to actual aversive stimulation may be a characteristic of combat veterans with PTSD," says J.P. Ginsberg, a member of the research team.

Additional tests in the study assessed subjects' short-term memory for verbal information and indicated that the ability to pay attention was disturbed in those with PTSD. Ginsberg and his colleagues found that deficits in PTSD combat veterans' ability to memorize new verbal information correlated to their rapid habituation, a result that links impairments in physiological and cognitive function as a result of the disorder.

"We may be able to relate these findings to central nervous system circuits involving the amygdala, cingulate cortex, and medial prefrontal cortex, all of which are known to be involved in brain processing of emotional material and which have been demonstrated to be dysfunctional in PTSD," says Ginsberg. He notes the same brain regions are involved in associative learning, physiological regulation of the heart, and attention to verbal information.

Animal research is aiming to advance the development of effective therapies for PTSD, and new findings based on studies with rats reveal how PTSD differs from other anxiety disorders -- and therefore why it can prove so hard to treat.

Michael Fanselow, PhD, at the University of California, Los Angeles, has developed a rat model using a regimen he calls stress-enhanced fear learning. He used this model to examine the way traumatic stress affects the capacity to learn and remember fear and to test proposed treatment approaches that focus on the timing and intensity of therapy.

Initially, the rats were placed in a room (A) and given a shock to the foot. The next day, in a separate setting (B), 15 shocks were administered over a 90-minute period, a traumatic level of stress. The rats were returned to the same room for 30 minutes on five subsequent days, but not exposed to shock. On the sixth day, the rats were placed in a third room (C), where again they received a single shock to the foot.

Tested in the two rooms in which they received the single shock, the rats acted far more fearful in setting C. "These findings indicate that fear learning that occurs after traumatic stress is markedly different from fear learning that occurs in other circumstances," Fanselow says.

The second part of the study tested the effectiveness of potential therapies focused on enhancing the extinction of terrifying memories. Using a method known as massed extinction, in which five 30-minute extinction sessions were held with five-minute intervals in between, Fanselow compared the effectiveness of the technique when administered 10 minutes and 72 hours after the traumatic event.

"Recent fear conditioning research suggests that massed extinction or extinction that starts immediately after conditioning may be especially effective at fear reduction," Fanselow says.

Once the mass extinction trial was finished, the rats received another single shock to the foot; their fear response was tested a day later. The rats treated with mass extinction were compared with an untreated group and one that had not been exposed to traumatic stress. All three groups with experience of traumatic stress responded similarly, suggesting that the massed extinction technique -- whether administered immediately after trauma or after an initial delay -- is not an effective treatment for PTSD.

The finding that stress-enhanced fear learning is not changed by various extinction methods, Fanselow notes, "may begin to explain why PTSD is so difficult to treat."

"Pavlovian fear conditioning is used in many animal models of fear learning and memory," says Fanselow. "These animal models have been very successful at helping to understand the nature of anxiety disorders and have furthered knowledge such that it has benefited human research on course and treatment.

"In the case of animal models of PTSD, however, we propose that the stress-enhanced fear learning model produces symptoms more similar to those found in PTSD than other animal models."