NEWARK, NJ – The National Institute of Mental Health estimates that in any given year, about 40 million adults (18 or older) will suffer from some form of anxiety disorder, including debilitating conditions such as phobias, panic disorders and post-traumatic stress disorder (PTSD). It is estimated that nearly 15 percent of U.S. soldiers returning from Iraq and Afghanistan develop PTSD, underscoring the urgency to develop better treatment strategies for anxiety disorders. These disorders can lead to myriad problems that hinder daily life – or ruin it altogether – such as drug abuse, alcoholism, marital problems, unemployment and suicide.

Functional imaging studies in combat veterans have revealed that the amygdala, a cerebral structure of the temporal lobe known to play a key role in fear and anxiety, is hyperactive in PTSD subjects. Potentially paving the way for more effective treatments of anxiety disorders, a recent Nature report by Denis Paré, professor at the Center for Molecular and Behavioral Neuroscience at Rutgers University in Newark, has identified a critical component of the amygdala’s neural network normally involved in the extinction, or elimination, of fear memories. Paré’s laboratory studies the amygdala and how its activity impacts behavior. His research was published online by Nature on July 9, 2008 and is scheduled to appear in the print edition later in July.

Earlier research has revealed that in animals and humans, the amygdala is involved in the expression of innate fear responses, such as the fear of snakes, along with the formation of new fear memories as a result of experience, such as learning to fear the sound of a siren that predicts an air raid.

In the laboratory, the circuits underlying learned fear are typically studied using an experimental paradigm called Pavlovian fear conditioning. In this research model on rats, a neutral stimulus such as the sound of a tone elicited a fear response in the rats after they heard it paired with an noxious or unpleasant stimulus, such as a shock to the feet. However, this conditioned fear response was diminished with repetition of the neutral stimulus in the absence of the noxious stimulus. This phenomenon is known as extinction. This approach is similar to that used to treat human phobias, where the subject is presented with the feared object in the absence of danger.

Behavioral studies have demonstrated, however, that extinction training does not completely abolish the initial fear memory, but rather leads to the formation of a new memory that inhibits conditioned fear responses at the level of the amygdala. As such, fear responses can be expressed again when the conditioned stimulus is presented in a context other than the one where extinction training took place.

For example, suppose a rat is trained for extinction in a grey box smelling of roses, and later hears the tone again in a different box, with a different smell and appearance. The rat will show no evidence of having been trained for extinction. The tone will evoke as much fear as if the rat had not been trained for extinction.

“Extinction memory will only be expressed if tested in the same environment where the extinction training occurred, implying that extinction does not erase the initial fear memory but only suppresses it in a context-specific manner,” notes Paré.

Importantly, it has been found that people with anxiety disorders exhibit an “extinction deficit,” or a failure to “forget.” However, until recently, the mechanisms of extinction have remained unknown.

As reported by Nature, Paré has found that clusters of amygdala cells, known as the intercalated (ITC) neurons, play a key role in extinction. His findings indicate that ITC cells inhibit amygdala outputs to the brain stem structures that generate fear responses. Indeed, Paré and his collaborators have shown that when ITC cells are destroyed with a targeted toxin in rats, extinction memory is impeded, mimicking the behavior seen in PTSD.

The significance of this finding derives from earlier results suggesting that PTSD reflects an extinction deficit and that the amygdala is hyperactive in this disorder. As a result, it might be possible to compensate for this abnormality and facilitate extinction with pharmacological interventions that enhance the excitability of ITC cells to inhibit amygdala output.

Soldiers returning from combat in Iraq who have migraine headaches are more than twice as likely to also have symptoms of post-traumatic stress, depression or anxiety than soldiers who do not have migraines, according to research that will be presented at the American Academy of Neurology’s 59th Annual Meeting in Boston, April 28 – May 5, 2007.

The study involved 3,621 United States Army soldiers who were given a health screening questionnaire within 90 days after returning from one year of combat duty in Iraq. A total of 2,167 of the soldiers, or 60 percent, completed the questionnaire. Of those, 19 percent screened positive for migraine headaches, 32 percent screened positive for depression, 22 percent screened positive for post-traumatic stress disorder, and 13 percent screened positive for anxiety.

The researchers found that 50 percent of those with migraine also had depression, compared to 27 percent of those without migraine. A total of 39 percent of those with migraine also had post-traumatic stress disorder, compared to 18 percent of those without migraine. And 22 percent of those with migraine also had anxiety, compared to 10 percent of those without migraine.

“Previous studies in non-military populations had revealed a higher prevalence of certain psychiatric conditions, such as depression and anxiety, among people with migraine,” said study author Maj. Jay C. Erickson, MD, PhD, of Madigan Army Medical Center in Tacoma, WA. “We hypothesized that there would be a similar relationship between migraine and psychiatric conditions in soldiers. The precise reasons for such an association are not fully understood, but may be related to similarities in the mechanisms underlying migraines and some psychiatric disorders.”

The study also found that those with migraine and depression also had more frequent headaches than those who had migraine with no depression – an average of 3.5 headache days per month for those with depression compared to 2.5 days per month for those with no depression. The findings were similar for those with migraine and post-traumatic stress disorder.

“These findings should alert health care providers, especially those affiliated with the military or veteran health care systems, about the frequent association of migraine headaches and psychiatric conditions in soldiers returning from deployment,” Erickson said. “We recommend that health care providers who evaluate combat veterans for headaches perform mental health screening in order to ensure that psychiatric disorders are identified and properly treated. All soldiers returning from deployment presently undergo mental health screening.”