Dr. Marmar presented preliminary findings from 52 PTSD cases and 52 controls that were matched for sex, ethnicity, and age. The sample was entirely men, their mean age was 34 years, and they had a mean of 14.8 years of education. The researchers covaried for depression and other known confounders. “It’s very difficult to disentangle the effects of PTSD and depression because 50% of the cases of warzone PTSD also meet criteria for current major depression, and over 80% meet criteria for lifetime depression,” he said.
In results from the clinical diagnostic evaluation, PTSD cases, compared with controls, were significantly more likely to have current anxiety (7% vs. 0%, respectively; P = .041); lifetime anxiety (9.6% vs. 0%; P = .022); current major depressive disorder (51.5% vs. 1.9%; P<.001); lifetime MDD (84.6% vs. 23.1%; P<.001); and lifetime alcohol abuse dependence (63.5% vs. 25%; P = .001). There was also a non-signficant trend toward lifetime substance abuse/dependence (13.5% vs. 3.9%; P = .081).
Results from the neurocognitive assessments revealed that PTSD positive men had a significantly lower estimated IQ, compared with their PTSD negative counterparts (a mean of 99.3 vs. 107.9, respectively; P = .031). Other significant differences between the two groups were observed in tests of auditory and working memory, specifically digit span (8.67 vs. 10.04; P = .02), and the visual memory sum (9.1 vs. 10.67; P = .01).
One of the consortium collaborators developed a test to compare reward and punishment learning. For the test, “the subject is required to understand what the meaning of a symbol is in a task, and they have no prior knowledge [of the meaning],” Dr. Marmar explained. “They’re either rewarded for guessing correctly or punished for guessing incorrectly.” So far, the healthy controls “are performing much better in identifying the symbols when they’re rewarded, compared with the PTSD cases, and there’s no difference in punishment,” he said. “So there’s impaired reward learning and intact punishment learning in PTSD cases compared to controls, which likely reflects underlying disturbances in dopamine reward circuitry.”
Investigators in the neurogenetics core hypothesized that DNA variants in stress-response genes identified from previous medical studies will be associated with PTSD. These included FKBP5, COMT, APOE, BDNF, PACAP/PAC1R, and OPRL1. Initial analysis revealed that there were a greater number of BDNF allele frequencies among cases, compared with controls (P = .008). “It would appear that BDNF variants confer resilience for combat-related PTSD,” Dr. Marmar said.
The researchers also found a single nucleotide polymorphism never previously described on Chromosome 4. “It’s in a region between genes, probably a micro-RNA regulatory gene on the 4th chromosome,” he said. “That gene in our sample was associated with higher levels of PTSD. In addition, fMRI studies found that carrying this allele was associated with weaker activation of prefrontal cortical areas in the brain to empirical faces tasks.”
The endocrine core found that PTSD cases had lower ambient cortisol levels, compared with controls (P = .051). They also had significantly greater cortisol suppression following dexamethasone administration, compared with controls (P = .013). “This is evidence that there is increased glucocorticoid receptor sensitivity in PTSD expressing as elevated cortisol suppression,” Dr. Marmar said.
Investigators from the structural imaging core found no significant differences in overall hippocampal volume or in the five major hippocampal subfields between PTSD cases and controls, nor in difference in the volume of other brain structures previously implicated in PTSD, such as the amygdala and the thalamus. However, the researchers are finding some differences between cases and controls on functional imaging, including increased spontaneous activity in the amygdala and the insula, and decreased spontaneous activity in the precuneus. “The overall findings on fMRI are that there’s increased activity in the regions [of the brain] associated with fear and decreased connectivity between the frontal cortex and the amygdala,” he said. “This is consistent with the model of dysregulated fear activity in PTSD.”
Researchers have also observed that many markers of metabolic syndrome are significantly elevated between PTSD cases and controls, including fasting glucose (P = .001), weight (P = .03), and resting pulse (P = .003). “When you covary for depression, these findings remain,” Dr. Marmar said. “It’s important to note that these are men mostly in their early 30s recently returned from war and recently in military training, physically fit to be deployed to war.”
He closed his presentation by noting that mounting evidence from animal and human studies suggests evidence of mitochondrial dysfunction in PTSD. In the current analysis, researchers observed a reduced abundance of citrate and other mitochondrial metabolites in PTSD cases compared with controls, as well as an increased abundance of “premitochondrial” metabolites such as pyruvate and lactate. “These findings stand when you covary for depression and for metabolic syndrome,” Dr. Marmar said.