Disruption of Bradycardia During Vigilance: Autonomic Cardiac Dysregulation is Prelude to Disinhibition, Hyperarousal, and Attention Bias in Combat Veterans with PTSD

We propose a model to account for the post‐traumatic stress disorder (PTSD) symptoms of disinhibition, hyperarousal, and attention bias. We review the background literature which is the foundation on which our model rests, present key results of our ongoing research, and suggest testable hypotheses for further research. Our laboratory is in a Veterans Affairs (VA) Medical Center, where we began our work with a search for the significant causes and predictors of hyperarousal in combat veterans with PTSD using eyeblink and autonomic conditioning protocols. We believe our studies will lead to integration of a treatment intervention for war veterans (and equally as well for treatment of the traumatically stressed in the general population). Our research has begun to show strong associations between lowered heart rate variability (HRV) and PTSD. Loss of bradycardia during normal vigilance is the cause of lowered HRV, which impairs appraisal of threat value of environmental stimulation, thereby leading to disinhibition, hyperarousal, and attention bias toward and away from threat. The next steps of research we plan are outlined and designed to elucidate how HRV biofeedback is a promising intervention to increase HRV during vigilance of stimuli and restore cognitive appraisal and response selection, thereby reducing PTSD symptoms and normalizing behavior

Plasma BDNF Levels Vary in Relation to Body Weight in Females

Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression as well as neuropsychiatric and neurodegenerative disorders. Recent studies show a role of BDNF in energy metabolism and body weight regulation. We examined BDNF levels in plasma and cerebrospinal fluid (CSF) samples from age matched elderly depressed and control subjects. Also, the association of BDNF levels with age, gender, body weight, body mass index (BMI), and cognitive performance was evaluated. We did not find any significant differences in plasma and CSF BDNF levels between depressed and control subjects. Plasma BDNF levels were negatively correlated with age (but not with BMI and body weight), when analyses were performed including both depressed and control subjects. A significant reduction in plasma BDNF levels was observed in females as compared to male subjects, and the change in BDNF levels were significantly and positively related to body weight in females. Furthermore, significant increases in Total Recall and Delayed Recall values were found in females as compared to males. In conclusion, the lower BDNF levels observed in females suggest that changes in peripheral BDNF levels are likely secondary to an altered energy balance. However, further studies using larger sample size are warranted

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype

Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper

Disruption of bradycardia associated with discriminative conditioning in combat veterans with PTSD

Jay P Ginsberg1,2, Edwin Ayers3, Louisa Burriss1, Donald A Powell1,41Shirley L. Buchanan Neuroscience Laboratory, Dorn VA Medical Center, Columbia, SC, USA; 2Department of Pharmacology, Physiology, and Neuroscience, School of Medicine, 4Department of Psychology, University of South Carolina, Columbia, SC, USA; 3Department of Psychology, South Carolina State University, Orangeburg, SC, USAAbstract: The effects of combat-related posttraumatic stress disorder (PTSD) on heart rate (HR) responding associated with a discriminative delay eyeblink (EB) conditioning paradigm are reported. Combat PTSD+, Combat PTSD−, and Noncombat PTSD− veterans were assessed with psychometric self-report measures, and baseline heart rate variability (HRV) was measured before receiving a 72-trial session of discriminative EB classical conditioning. Two types (red or green light) of conditioned stimuli (CS) were used: one (CS+) predicted a tone, followed immediately by an aversive stimulus (corneal airpuff); the other (CS−) predicted a tone alone, not followed by the airpuff. The light signal was presented for 5 seconds, during which HR was measured. On all psychometric measures, the PTSD+ subgroup was significantly different from the PTSD− subgroups (Combat + Noncombat), and the PTSD− subgroups did not significantly differ from each other. A linear deceleration in HR to CS+ and CS− signals was found in the combined PTSD− subgroup and on CS− trials in the PTSD+ subgroup, but was not present on CS+ trials in the PTSD+ subgroup. Results are interpreted with respect to a behavioral stages model of conditioned bradycardia and in terms of neural substrates which are both critical to HR conditioning and known to be abnormal in PTSD.Keywords: bradycardia, PTSD, combat veterans, classical conditionin

Comparison of cytokines IFN-γ, IL-17, PDGF-bb, RANTES and IL-4inplasma from controls and PTSD patients.

<p>Plasma samples were isolated from peripheral blood samples of patients with PTSD and normal controls by centrifugation. Then, Bio-Rad Bio-Plex method was used to determine the concentrations of multiple cytokines (including IL-1β, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12(p70), IL-13, IL-15, IL-17, FGF-β, eotaxin, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α and VEGF). Wilcoxon rank sum test was used to compare the difference of cytokines in the plasma between controls and PTSD patients. Plasma levels of IFN-γ (<b>A</b>), IL-17 (<b>B</b>), PDGF-bb (<b>C</b>), and RANTES (<b>D</b>) were found to be significantly different between controls and PTSD patients, whereas other cytokines such as IL-4 (<b>E</b>) did not have significant difference in plasma from controls and PTSD patients. The boxed data included 50% of measurements at medium level, the line in the box was the average value and the data beyond the upper line were the outliers. <i>p</i> values were presented.</p

Dysregulation in miRNA expression profile in PBMC from PTSD patients and controls.

<p><b>A–F:</b> Total RNA from PBMC of patients with PTSD and normal controls were used in the analysis of miRNA expression by Affymetrix miRNA array hybridization. Comparison of miRNA expression profiles between individual controls and PTSD patients was shown by the heat map (<b>A</b>) and plot of the principal component analysis accounting for 60.1% variability (<b>B</b>). Seven up-regulated miRNAs in PBMC from PTSD patients were compared with those from controls (<b>C</b>). 64 down-regulated miRNA molecules (>2.5 fold change, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094075#pone-0094075-t001" target="_blank">Table 1</a>) in PBMC from PTSD patients were detected (<b>D</b>). Total RNA samples were also used in the confirmation of miRNA down-regulation (miR-125a and miR-181c) in PBMC from PTSD patients by real-time PCR (<b>E</b>). Wilcoxon rank sum test was used to compare the difference in miRNA expression in PBMC between controls and PTSD patients. <b>F–G:</b> Role of hsa-miR-125a in the regulation of IFN-γ. Complementary sequences between the seed sequence of miR-125a and 3′-untranslated region (3′UTR) of IFN-γ gene were compared (<b>F</b>). In silico studies were used to determine the complementary sequences between the seed sequence of miR-125a and 3′UTR of IFN-γ gene. The inhibitory effect of miR-125a on IFN-γ production in PBMC was determined (<b>G</b>). Hsa-miR-125a precursor (pre-miR125a) and pre-scramble control (scrambled premiR) were introduced into PBMC by electroporation. After PHA stimulation for two days, IFN-γ release from PBMC was determined in the culture supernatant by ELISA. Wilcoxon rank sum test was used to analyze the inhibitory effects of miR-125a on IFN-γ production in PBMC.</p

Pathway Analysis depicting a network of dysregulated miRNAs and target genes and their relationship in regulation of immune functions and pathways.

<p><b>A.</b> Dysregulated miRNAs from PTSD patients were found to be involved in immunological pathways when Ingenuity Pathway Analyses were performed. The green tags represent down-regulated miRNAs and red tags up-regulated miRNAs in PBMC from PTSD patients when compared to controls. Circles represent genes, ovals are transcriptional regulators, diamonds are enzymes and triangles are kinases. Solid arrows represent direct action and dashed arrows indirect action. <b>B.</b> Depicts the relationship between miRNAs from PTSD patients with their target genes. First, both upregulated and downregulated miRNAs of PTSD patients were selected following Ingenuity Pathway analysis and then the relationship between miRNAs and genes were analyzed using Cytoscape software. Cytoscape analysis showed relationship between miRNAs and immunological pathways, especially between miRNAs and cytokine-associated genes (IL-1RA, IL-2, IL-2RB, IFN-γ, IL-12, IL-10, IL-17, IL-17R, TGF-β, IL-23A, etc.) playing a role in T cell development and immune functions. The larger circles represent miRNAs that are involved in regulation of a large number of genes, when compared to miRNAs represented by smaller circles. <b>C.</b> Shows the role of dysregulated miRNAs from PTSD patients in various immunological mechanisms and pathways. Upregulated and down-regulated miRNAs from PTSD patients were analyzed using Cytoscape (ClueGo) software. miRNAs from PTSD patients were found to be involved in several immunological and biological pathways.</p