Neuroimaging Studies In PTSD
By J. Douglas Bremer, M.D.
NCP Clinical Quarterly 7(4): Fall 1997
With the growing appreciation for the biological basis of posttraumatic stress disorder (PTSD) there has been an increase in interest in neuroimaging studies of patients with PTSD. Neuroimaging studies include all studies which take advantage of radiological techniques to provide information about the structure and function of the brain.
The first radiologic studies in trauma patients used pneumoencephalography, which involves the injection of air into the cerebrospinal space, and imaging with the use of simple X-rays. This technique was applied to concentration camp survivors from World War II seeking compensation for disability. The authors reported "[cerebral] atrophy of varying degrees and " diffuse encephalopathy" in up to 81% of cases, based on their visual interpretation, although noquantitative measures of atrophy were performed (1).
Magnetic resonance imaging (MRI) is a technologically more advanced method of imaging than X-ray based techniques such as pneumoencephalography. MRI uses a powerful magnetic to throw the electrons and protons which make up brain tissue out of their normal patterns, and measures the time it takes for them to return to their normal resting state. This relaxation time says something about the content of the tissue, which can be used to create an image of the brain. MRI images are obtained of successive slices which move through the entire volume of the brain a few millimeters at a time. With specialized image processing software on the computer, the outline of individual brain regions in successive slices can be traced using a mouse driven cursor, and the volume within the outlines quantitated and converted to real brain volume. These techniques have been shown to be highly reliable in the hands of well trained operators, and have provided a wealth of information about brain structure in psychiatric disorders in general, and more recently in the field of PTSD.
Studies using MRI in PTSD have measured volume of the hippocampus, a brain structure involved in learning and memory. This line of research was prompted by studies in animals showing that high levels of cortisol seen in stress are associated with damage to the hippocampus. We compared hippocampal volume measured with MRI in Vietnam combat veterans with PTSD and healthy subjects matched for factors which could affect hippocampal volume, including age, sex, race, years of education, height, weight, handedness, and years of alcohol abuse. Patients with combat-related PTSD had an 8% decrease in right hippocampal volume in comparison to controls (p<0.05), but no significant decrease in volume of comparison structures including temporal lobe, amygdala or caudate. Deficits in free verbal recall (explicit memory) as measured by the Wechsler Memory Scale-Logical Component, percent retention, were associated with decreased right hippocampal volume in the PTSD patients (r=0.64; p<0.05) (2). Multivariate analyses performed to control for differences in alcohol abuse and education not completely controlled for by the matching strategy showed significant differences after controlling for these variables. Gurvits et al (3) found a significant reduction in hippocampal volume bilaterally in males with combatñrelated PTSD. Our group found a statistically significant 12% decrease in left hippocampal volume in 17 patients with a history of PTSD related to severe childhood physical and sexual abuse, in relationship to 17 controls matched on a case-by-case‹basis with the patients (4). Stein et al (5) found a reduction in left hippocampal volume in women with childhood sexual abuse compared to women without childhood sexual abuse. Reduced hippocampal volume correlated with dissociative symptomatology in this study (r=-0.73).
Positron emission tomography (PET) can be used to provide a measure of brain function, measured with brain blood flow and metabolism. Glucose is the primary energy source of the brain, and when there is an increase in firing of the neurons in a specific brain region, there is an increase in glucose uptake in that region to meet the demand. Similary, with increased glucose demand there is an increase of brain blood flow to that region. With a regional increase in neuronal activity (for instance, in the visual cortex following exposure to a bright light), there is a shunting of blood flow with accompanying drop in glucose toward that region which can be measured with PET as a "real time" measure of brain function.
The radioactive substances used in PET can be prepared in an on site cyclotron and injected immediately into the patient for imaging. Brain blood flow is measured with radioactive water H2[O-15], and brain metabolism with radioactive glucose ([18F]2 fluoro-2-deoxyglucose, or FDG). These substances emit positrons in the course of radioactive decay, which collide with electrons in the brain, creating two beams of light which travel away from each other and are "detected" by the camera. Computers then use this information to reconstruct an image of thebrain's metabolism or blood flow patterns.
We used PET and FDG in the measurement of cerebral glucose metabolic rate following administration of yohimbine and placebo in Vietnam combat veterans with PTSD and healthy controls. Increased noradrenergic function has been hypothesized to underlie many of the symptoms of PTSD, and administration of the alpha-2 antagonist, yohimbine, which stimulates brain norepinephrine release, to patients with PTSD results in increased PTSD symptoms and anxiety. Norepinephrine has a U-shaped curve type of effect on brain function, with lower levels of release causing an increase in metabolism, while very high levels of release actually cause a decrease in metabolism. We hypothesized that yohimbine would cause a relative decrease in metabolism in patients with PTSD in cortical brain areas which receive noradrenergic innervation. Consistent with this hypothesis, yohimbine resulted in a relative decrease in metabolism in orbitofrontal, temporal, parietal, and prefrontal cortex, in PTSD patients relative to controls (6). These findings are consistent with an increased release of norepinephrine in the brain following yohimbine in PTSD.
Studies have begun to use PET to identify brain regions which mediate traumatic remembrance and physiological reactivity to traumatic cues. These studies have typically started from the hypothesis that an increase in activity of limbic brain regions involved in emotion following exposure to traumatic cues is characteristic of PTSD. Three studies to date have used varying behavioral protocols, and consequently the results are slightly different. Rauch et al (7) used PET and H20[150] to look at blood flow during exposure to traumatic and neutral scripts in a group of PTSD patients. Exposure to traumatic scripts resulted in an increase in brain blood flow in limbic regions (right amygdala, insula, orbitofrontal cortex, and anterior cingulate), and decreased blood flow in middle temporal and left inferior frontal cortex. Our group studied Vietnam veterans with and without PTSD during exposure to combat-related and neutral slides and sounds. Vietnam veterans with combat-related PTSD demonstrated a relative failure of activation of orbitofrontal cortex with combat-related slides and sounds in comparison to Vietnam combat veterans without PTSD. Exposure to combat slides resulted in a relative increase in blood flow in two limbic regions, lingual gyrus (posterior parahippocampus) and mid-cingulate. There were also activations in several nonhypothesized regions, including parietal and motor cortex, and dorsal pons. Shin et al (8) used PET and H20[150] during induction of combat trauma-related and neutral mental imagery in patients with PTSD and healthy controls. This study found a relative failure of orbitofrontal cortex activation, increased blood flow in two hypothesized limbic regions, right amygdala and anterior cingulate, as well as decreased blood flow in middle temporal and left inferior frontal cortex in PTSD patients (but not controls) during exposure to mental imagery (8).
A failure of extinction to fear is an important part of the presentation of PTSD. The neural mechanism of extinction to fear involves orbitofrontal cortex inhibition of amygdala function. Reexposure to the unconditioned-conditioned stimulus pairing results in a rapid return of the conditioned fear response, which suggests that the information was present in the amygdala but merely inhibited by orbitofrontal cortex inhibition. Exposure of PTSD patients to trauma-related material, or traumatic imagery, results in an increase in fearfulness in response to stimuli which were not truly life threatening, possibly due to a failure of orbitofrontal function. In our study, combat veterans without PTSD (unlike the PTSD patients) were able to view combat slides and not have an increase in fearfulness, which we hypothesized is due to active orbitofrontal inhibition of amygdala function. Shin et al (8) also found a relative failure of orbitofrontal activation with traumatic imagery. Our prior PET yohimbine study (6) showed a failure of orbitofrontal cortex with pharmacologic stress in PTSD. Rauch et al (7) found increased orbitofrontal activation with traumatic scripts with their PTSD patients, althought this study did not involve a control group, so it is not possible to determine whether a greater increase in orbitofrontal blood flow would be seen in subjects without PTSD. All of these PET studies found a relative decrease in middle temporal blood flow with combat slides and sounds in PTSD patients. The middle temporal cortex also plays a role in the extinction to fear through inhibition of amygdala function.
The parahippocampus was also found to activate with traumatic reminders across groups. In our study, it involved a posterior portion of the parahippocampus, the lingual gyrus, which has been specifically implicated in visual processing. The cingulate was found to activate in all studies, an area of mid-cingulate in our subjects, and anterior cingulateis in the other groups. Cingulate is a limbic region involved in memory, emotion, and attention in the service of selection for action. The fact that some brain regions did not show activation in all of the studies reviewed above is not surprising, considering the differences in tasks involved in each study. Future research may show that traumatic exposure involves specific regions, regardless of the task, while other regions are task specific. For instance, other groups (but not our group) found activation in amygdala and a decrease in left inferior frontal gyrus activity with traumatic exposure. These findings were seen only with traumatic imagery, however, and not with presentation of traumatic pictures (8). It may be that a decrease in activity in this area (as well as activation of the amygdala) is specific to the generation of mental images of the traumatic event, and is not seen during presentation of pictures of traumatic events or with exposure to the combination of traumatic pictures and sounds.
Several studies are ongoing in the rapidly expanding area of functional imaging in PTSD. Semple and colleagues at Case Western Reserve are studying brain correlates of attention in patients with PTSD and comorbid substance abuse. Engahl and colleagues at the University of Minnesota are using single photon emission computed tomography (SPECT) to study brain correlates of script driven imagery in PTSD. Liebowitz and colleagues at the University of Michigan are looking brain activation with SPECT following exposure to combatñrelated sounds in PTSD patients and controls. Results of some of these studies have been presented at scientific meetings.
References
1. Thygesen, P., Hermann, K., & Willanger, R. (1970). Concentration camp survivors in Denmark: Persecution, disease, disability, compensation. Danish Medical Bulletin, 17, 65-108.
2. Bremner, J.D., Randall, P.R., Scott, T.M., Bronen, R.A., Delaney, R.C., Seibyl, J.P., Southwick, S.M., McCarthy, G., Charney, D.S., & Innis, R.B. (1995). MRI-based measurement of hippocampal volume in posttraumatic stress disorder. American Journal of Psychiatry, 152, 973-981.
3. Gurvits, T.G., Shenton, M.R., Hokama, H., Ohta, H., Lasko, N.B., Gilbertson, M.W., Orr, S.P., Kikinis, R., Jolesz, F.A., McCarley, R.W., & Pitman, R.K. (1996). Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biological Psychiatry, 40, 1091-1099.
4. Bremner, J.D., Randall, P., Vermetten, E., Staib, L., Bronen, R.A., Mazure, C.M., Capelli, S., McCarthy, G., Innis, R.B., & Charney, D.S. (1997). MRI-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse: A preliminary report. Biological Psychiatry, 41, 23-32.
5. Stein, M.B., Koverola, C., Hanna, C., Torchia, M.G., & McClarty, B. (1997). Hippocampal volume in women victimized by childhood sexual abuse. Psychological Medicine, 27, 951-959.
6. Bremner, J.D., Innis, R.B., Ng, C.K., Staib, L., Duncan, J., Bronen, R., Zubal, G., Rich, D., Krystal, J.H., Dey, H., Soufer, R., & Charney, D.S. (1997). PET measurement of central metabolic correlates of yohimbine administration in posttraumatic stress disorder. Archives of General Psychiatry, 54, 246-256.
7. Rauch, S.L., van der Kolk, B.A., Fisler, R.E., Alpert, N.M., Orr, S.P., Savage, C.R., Fischman, A.J., Jenike, M.A., Pitman, R.A. (1996). A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script driven imagery. Archives of General Psychiatry, 53, 380-387.
8. Shin, L.M., Kosslyn, S.M., McNally, R.J., Alpert, N.M., Thompson, W.L., Rauch, S.L., Macklin, M.L., & Pitman, R.K. (1997). Visual imagery and perception in posttraumatic stress disorder: A positron emission tomographic investigation. Archives of General Psychiatry, 54, 237-233.
J. Douglas Bremner is a research physician at VA Connecticut Healthcare System, National Center for PTSD Neuroscience Divison at West Haven. Dr. Bremner is also Director, Trauma Assessment Unit, Yale Psychiatric Institute and an Assistant Professor of Diagnostic Radiology and Psychiatry at Yale University School of Medicine.
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