Faculty Bibliography

A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.

BACKGROUND AND OBJECTIVES/OBJECTIVE:It has been proposed that self-efficacy plays a critical role in the onset and maintenance of Posttraumatic Stress Disorder (PTSD). This study aimed to test if increasing perceptions of self-efficacy using a false feedback technique about coping abilities prior to a trauma-film paradigm lead to a reduction of visual intrusions over the course of 6 days. DESIGN AND METHODS/METHODS:Healthy participants recruited from the community were randomized to a high self-efficacy (HSE, N = 18), low self-efficacy (LSE, N = 21), or neutral self-efficacy (NSE, N = 23) conditions. RESULTS:Participants in the HSE condition reported higher levels of self-efficacy. In addition, individuals in the HSE conditions reported significantly fewer intrusions over 6 days. Unexpectedly, individuals in the LSE condition reported fewer intrusions on the final day of the study compared to those in the NSE condition. The LSE group was also the only group showing a significant linear decline in intrusion across the 6 days. DISCUSSION/CONCLUSIONS:These findings provide further support that perceptions of self-efficacy are modifiable and may contribute to clinically-relevant processes underlying PTSD. Future prospective research with individuals exposed to trauma will help to shed light on the potential role of self-efficacy to buffer the negative impacts of traumatic stress.

Posttraumatic stress disorder (PTSD) is associated with impaired major domains of psychology and behavior. Individuals with PTSD also have increased co-morbidity with several serious medical conditions, including autoimmune diseases, cardiovascular disease, and diabetes, raising the possibility that systemic pathology associated with PTSD might be identified by metabolomic analysis of blood. We sought to identify metabolites that are altered in male combat veterans with PTSD. In this case-control study, we compared metabolomic profiles from age-matched male combat trauma-exposed veterans from the Iraq and Afghanistan conflicts with PTSD (n = 52) and without PTSD (n = 51) ('Discovery group'). An additional group of 31 PTSD-positive and 31 PTSD-negative male combat-exposed veterans was used for validation of these findings ('Test group'). Plasma metabolite profiles were measured in all subjects using ultrahigh performance liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry. We identified key differences between PTSD subjects and controls in pathways related to glycolysis and fatty acid uptake and metabolism in the initial 'Discovery group', consistent with mitochondrial alterations or dysfunction, which were also confirmed in the 'Test group'. Other pathways related to urea cycle and amino acid metabolism were different between PTSD subjects and controls in the 'Discovery' but not in the smaller 'Test' group. These metabolic differences were not explained by comorbid major depression, body mass index, blood glucose, hemoglobin A1c, smoking, or use of analgesics, antidepressants, statins, or anti-inflammatories. These data show replicable, wide-ranging changes in the metabolic profile of combat-exposed males with PTSD, with a suggestion of mitochondrial alterations or dysfunction, that may contribute to the behavioral and somatic phenotypes associated with this disease.

Peripheral Blood gene expression is widely used in the discovery of biomarkers and development of therapeutics. Recently, a spate of commercial blood collection and preservation systems have been introduced with proprietary variations that may differentially impact the transcriptomic profiles. Comparative analysis of these collection platforms will help optimize protocols to detect, identify, and reproducibly validate true biological variance among subjects. In the current study, we tested two recently introduced whole blood collection methods, RNAgard® and PAXgene® RNA, in addition to the traditional method of peripheral blood mononuclear cells (PBMCs) separated from whole blood and preserved in Trizol reagent. Study results revealed striking differences in the transcriptomic profiles from the three different methods that imply ex vivo changes in gene expression occurred during the blood collection, preservation, and mRNA extraction processes. When comparing the ability of the three preservation methods to accurately capture individuals' expression differences, RNAgard® outperformed PAXgene® RNA, and both showed better individual separation of transcriptomic profiles than PBMCs. Hence, our study recommends using a single blood collection platform, and strongly cautions against combining methods during the course of a defined study.