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NEW STUDIES FIND POTENTIAL BIOMARKER FOR PTSD, MAKE GAINS IN UNDERSTANDING DISORDER AND WHY IT IS DIFFICULT TO TREAT
November 6, 2007
SAN DIEGO, November 6, 2007 - New research identifies a characteristic
physiological response in veterans with post-traumatic stress disorder (PTSD)
that could be used as a biomarker to diagnose the disease. Other findings show
how trauma disables normal brain functioning and highlight deficits in basic
mechanisms of learning and memory. Recent findings also show that a common
neurological basis explains altered emotional responses in veterans with PTSD,
and that fear learning caused by trauma is different from other types and may
explain why it is more 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."
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