Panel: Encountering Daily Life:
Dennis S. Charney, M.D., is Professor of Psychiatry and Deputy Chair for Academic and Scientific Affairs at Yale University. He is the director of the NIMH-funded Yale Mental Health Clinical Research Center and the VA-funded National Center for Post-Traumatic Stress Disorder, Clinical Neuroscience Division.
Two questions are key to understanding post-traumatic stress disorder (PTSD):
To answer these questions, we need to know how sensory stimuli enter the brain, how they are processed, and which systems lead either to adaptive behavior or to symptoms of illness.
Of the many structures involved in processing experiences and turning them into memory, the key areas implicated in processing threatening or traumatic stimuli include the amygdala, the hippocampus, the locus coeruleus, and the orbital frontal cortex.
In one study, researchers exposed PTSD patients to stimuli associated with their trauma and used PET imaging to look at which parts of the brain were activated. The patients also were exposed to more neutral stimuli to see the difference in response. They found that the amygdala was activated by exposure to the traumatic elements of the stimuli but not activated to the same degree by exposure to neutral stimuli.
Another study looked at individuals who were exposed to trauma but did not develop PTSD. In this control population, the orbital frontal cortex was highly activated compared to its activation in the PTSD patients. Since the orbital frontal cortex has inhibitory effects on the amygdala, it may be that if the orbital frontal cortex is not being activated, and is thus not inhibiting the amygdala, the individual is more likely to develop PTSD.
The locus coeruleus, the major norepinephrine-containing nucleus in the pons, is also implicated in the experience of anxiety and fear. A number of experiments with animals have shown that the locus coeruleus is activated by frightening stimuli and also by stimuli that are in some way threatening to the survival of the organism.
To test the possible role of the norepinephrine system in anxiety and fear in people, researchers have used a drug, yohimbine, to activate the system by blocking a specific receptor in the brain called the alpha-2 norepinephrine receptor. In one series of studies, we looked at patients who had PTSD as a result of combat exposure in the Vietnam War. We found that they were very sensitive to the behavioral, biochemical, and cerebral metabolic effects of yohimbine, suggesting that their norepinephrine system was hyperreactive, even 20 to 25 years after their original trauma, and probably as a result of the trauma. A single dose of yohimbine, even in a laboratory setting, produced a variety of symptoms in these patients that evoke the original traumatic symptoms, including multisensory flashbacks. By contrast, the drug has no behavioral effect on normal healthy subjects.
Studies have shown that norepinephrine has a major role in the encoding of traumatic memories as opposed to more neutral memories. When propranolol, a beta adrenergic receptor antagonist drug used to treat high blood pressure, is given to healthy subjects, it can prevent or attenuate the encoding of the traumatic elements of a story, a finding that has important implications for treatment and perhaps prevention. Clinical trials are about to begin to test whether giving a drug like propranolol to a trauma victim soon after the incident can prevent PTSD.
Corticotropin-releasing factor (CRF), a key element in the slow-acting stress response known as the HPA (hypothalamus-pituitary-adrenal) axis, is involved in triggering the release of the stress hormone ACTH and cortisol. It also produces anxiety-related phenomena in laboratory animals.
A variety of work suggests that the CRF system is probably involved in PTSD. Several studies with nonhuman primates show that this system may be significantly altered, with long-term consequences, if an individual is exposed to stress very early in life and perhaps even prenatally.
This may have important implications for children born to mothers who are under a variety of stressors during pregnancy, including drug abuse, and for infants raised in adversive environments. Studies of adult PTSD patients find elevated levels of CRF even two decades after their traumatic experience.
What effect, then, does stress have on the brain? Work in a number of laboratories, with monkeys, tree shrews, and rodents has shown that exposure to stress--even fairly brief exposure--can produce changes in the hippocampus, including atrophy and irreversible cell death. In one very important study published earlier this year, stress has been shown to stop normal neurogenesis, or new cell growth, of dentate gyrus neurons in the hippocampus of adult monkeys.
These findings may have implications for patients with PTSD. Several MRI studies have shown reduced hippocampal volume in patients with PTSD as well as in victims of early trauma. We do not know yet if this reduced volume relates to the findings about hippocampal neurogenesis.
The work that I have described is so informative in helping us understand PTSD because preclinical neuroscientists have accomplished so much in their identification of the neurocircuits and neurochemistry and neuromechanisms involved in anxiety and fear. These are important clues to preventing and treating PTSD.
If you have questions or comments on the LC/NIMH Decade of the Brain Project, please contact: [email protected].
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