Relations of combat stress and posttraumatic stress disorder to 24-h plasma and cerebrospinal fluid interleukin-6 levels and circadian rhythmicity.

BACKGROUND: Acute and chronic stress can lead to a dysregulation of the immune response. Growing evidence suggests peripheral immune dysregulation and low-grade systemic inflammation in posttraumatic stress disorder (PTSD), with numerous reports of elevated plasma interleukin-6 (IL-6) levels. However, only a few studies have assessed IL-6 levels in the cerebrospinal fluid (CSF). Most of those have used single time-point measurements, and thus cannot take circadian level variability and CSF-plasma IL-6 correlations into account. METHODS: This study used time-matched, sequential 24-h plasma and CSF measurements to investigate the effects of combat stress and PTSD on physiologic levels and biorhythmicity of IL-6 in 35 male study volunteers, divided in 3 groups: (PTSD = 12, combat controls, CC = 12, and non-deployed healthy controls, HC = 11). RESULTS: Our findings show no differences in diurnal mean concentrations of plasma and CSF IL-6 across the three comparison groups. However, a significantly blunted circadian rhythm of plasma IL-6 across 24 h was observed in all combat-zone deployed participants, with or without PTSD, in comparison to HC. CSF IL-6 rhythmicity was unaffected by combat deployment or PTSD. CONCLUSIONS: Although no significant group differences in mean IL-6 concentration in either CSF or plasma over a 24-h timeframe was observed, we provide first evidence for a disrupted peripheral IL-6 circadian rhythm as a sequel of combat deployment, with this disruption occurring in both PTSD and CC groups. The plasma IL-6 circadian blunting remains to be replicated and its cause elucidated in future research.

Circadian rhythmicity, variability and correlation of interleukin-6 levels in plasma and cerebrospinal fluid of healthy men.

BACKGROUND: Interleukin-6 (IL-6) is a cytokine with pleiotropic actions in both the periphery of the body and the central nervous system (CNS). Altered IL-6 secretion has been associated with inflammatory dysregulation and several adverse health consequences. However, little is known about the physiological circadian characteristics and dynamic inter-correlation between circulating and CNS IL-6 levels in humans, or their significance. METHODS: Simultaneous assessment of plasma and cerebrospinal fluid (CSF) IL-6 levels was performed hourly in 11 healthy male volunteers over 24h, to characterize physiological IL-6 secretion levels in both compartments. RESULTS: IL-6 levels showed considerable within- and between-subject variability in both plasma and CSF, with plasma/CSF ratios revealing consistently higher levels in the CSF. Both CSF and plasma IL-6 levels showed a distinctive circadian variation, with CSF IL-6 levels exhibiting a main 24h, and plasma a biphasic 12h, circadian component. Plasma peaks were roughly at 4 p.m. and 4 a.m., while the CSF peak was at around 7 p.m. There was no correlation between coincident CSF and plasma IL-6 values, but evidence for significant correlations at a negative 7-8h time lag. CONCLUSIONS: This study provides evidence in humans for a circadian IL-6 rhythm in CSF and confirms prior observations reporting a plasma biphasic circadian pattern. Our results indicate differential IL-6 regulation across the two compartments and are consistent with local production of IL-6 in the CNS. Possible physiological significance is discussed and implications for further research are highlighted.

Characterization of cerebrospinal fluid (CSF) and plasma NPY levels in normal volunteers over a 24-h timeframe.

Neuropeptide Y (NPY) is abundant in mammals, where it contributes to diverse behavioral and physiological functions, centrally and peripherally, but little information is available in regard to NPY cerebrospinal fluid (CSF)/plasma concentration relationships and dynamics. Since plasma NPY levels are commonly used as proxy "biomarkers" for central NPY activity in stress and mental health research in humans this study aims to better characterize the CSF/plasma NPY relationships. Subjects were eleven healthy male volunteers, admitted to the clinical research center for placement of an indwelling CSF catheter, as well as venous catheter, for 24-h collection of CSF NPY (cNPY) and plasma NPY (pNPY) samples. As observed in prior studies, group mean (SE) cNPY concentrations [792.1 (7.80) pg/mL] were higher than pNPY concentrations [220.0 (3.63) pg/mL]. For the eleven normal volunteers who had sufficient common (hourly) pNPY and cNPY data points, analysis of pNPY/cNPY concentration ratios and lagged cross-correlation analysis was completed. Average pNPY/cNPY concentration ratios ranged from .20 to .40 across study subjects, with a mean of .29. pNPY/cNPY cross correlation analyses, computed at varying time lags, were non-significant. An attempt was made to analyze the circadian rhythmicity of NPY secretion, but circadian components were not detectable. Using 24-h data collection, we characterized CSF/plasma NPY relationships, including presentation of evidence of weak CSF and plasma correlations, an important consideration for study design of NPY in stress or mental health.

Diminished vagal activity and blunted diurnal variation of heart rate dynamics in posttraumatic stress disorder.

Affected autonomic heart regulation is implicated in the pathophysiology of cardiovascular diseases and is associated with posttraumatic stress disorder (PTSD). However, although sympathetic hyperactivation has been repeatedly shown in PTSD, research has neglected parasympathetic function. The objective of this study is the long-term assessment of heart rate (HR) dynamics and its diurnal changes as an index of autonomic imbalance in PTSD. Since tonic parasympathetic activity underlies long-range correlation of heartbeat interval fluctuations in the healthy state, we included nonlinear (unifractal) analysis as an important and sensitive readout to assess functional alterations. We conducted electrocardiogram recordings over a 24-h period in 15 deployed male subjects with moderate to high levels of combat exposure (PTSD: n = 7; combat controls: n = 8) in the supine position. HR dynamics were assessed in two 5-h sub-epochs in the time and frequency domains, and by nonlinear analysis based on detrended fluctuation analysis. Psychiatric symptoms were assessed using structured interviews, including the Clinician Administered PTSD Scale. Subjects with PTSD showed significantly higher baseline HR, higher LF/HF ratio in the frequency domain, blunted differences between day and night-time measures, as well as a higher scaling coefficient αfast during the day, indicating diminished tonic parasympathetic activity. Diminished diurnal differences and blunted tonic parasympathetic activity altering HR dynamics suggest central neuroautonomic dysregulation that could represent a possible link to increased cardiovascular disease in PTSD.

The association of posttraumatic stress disorder and metabolic syndrome: a study of increased health risk in veterans.

BACKGROUND: There is accumulating evidence for a link between trauma exposure, posttraumatic stress disorder (PTSD) and diminished health status. To assess PTSD-related biological burden, we measured biological factors that comprise metabolic syndrome, an important established predictor of morbidity and mortality, as a correlate of long-term health risk in PTSD. METHODS: We analyzed clinical data from 253 male and female veterans, corresponding to five factors linked to metabolic syndrome (systolic and diastolic blood pressure, waist-to-hip ratio and fasting measures of high-density lipoprotein (HDL) cholesterol, serum triglycerides and plasma glucose concentration). Clinical cut-offs were defined for each biological parameter based on recommendations from the World Health Organization and the National Cholesterol Education Program. Controlling for relevant variables including sociodemographic variables, alcohol/substance/nicotine use and depression, we examined the impact of PTSD on metabolic syndrome using a logistic regression model. RESULTS: Two-fifths (40%) of the sample met criteria for metabolic syndrome. Of those with PTSD (n = 139), 43% met criteria for metabolic syndrome. The model predicted metabolic syndrome well (-2 log likelihood = 316.650, chi-squared = 23.731, p = 0.005). Veterans with higher severity of PTSD were more likely to meet diagnostic criteria for metabolic syndrome (Wald = 4.76, p = 0.03). CONCLUSION: These findings provide preliminary evidence linking higher severity of PTSD with risk factors for diminished health and increased morbidity, as represented by metabolic syndrome.

Correlates for posttraumatic stress disorder in Gulf War veterans: a retrospective study of main and moderating effects.

With a sample of 120 Gulf War veterans, the present study investigated the main effects of childhood and lifetime trauma, combat exposure, and coping strategies on posttraumatic stress disorder (PTSD), as well as combat exposure's moderating effects on the other variables' relationships with PTSD. Logistic regression results indicated correct classification of PTSD diagnosis for 88% of the participants, with combat exposure and avoidant coping making significant contributions to this classification. Multiple regression results indicated that lifetime trauma, combat exposure, and avoidant coping were strongly related to PTSD symptoms. Multiple regression results also revealed that combat exposure moderated the strength and direction of PTSD's relationships with childhood trauma and avoidant coping. Study findings have implications for longitudinal investigation of PTSD development and preventive interventions.