Major Depressive Disorder and Chronic Fatigue Syndrome Show Characteristic Heart Rate Variability Profiles Reflecting Autonomic Dysregulations: Differentiation by Linear Discriminant Analysis.

Major depressive disorder (MDD) and chronic fatigue syndrome (CFS) have overlapping symptoms, and differentiation is important to administer the proper treatment. The present study aimed to assess the usefulness of heart rate variability (HRV) indices. Frequency-domain HRV indices, including high-frequency (HF) and low-frequency (LF) components, their sum (LF+HF), and their ratio (LF/HF), were measured in a three-behavioral-state paradigm composed of initial rest (Rest), task load (Task), and post-task rest (After) periods to examine autonomic regulation. It was found that HF was low at Rest in both disorders, but was lower in MDD than in CFS. LF and LF+HF at Rest were low only in MDD. Attenuated responses of LF, HF, LF+HF, and LF/HF to task load and an excessive increase in HF at After were found in both disorders. The results indicate that an overall HRV reduction at Rest may support a diagnosis of MDD. HF reduction was found in CFS, but with a lesser severity. Response disturbances of HRV to Task were observed in both disorders, and would suggest the presence of CFS when the baseline HRV has not been reduced. Linear discriminant analysis using HRV indices was able to differentiate MDD from CFS, with a sensitivity and specificity of 91.8% and 100%, respectively. HRV indices in MDD and CFS show both common and different profiles, and can be useful for the differential diagnosis.

Application of autonomic nervous function evaluation to job stress screening.

The present study focuses on the evaluation of autonomic nervous function, which is increasingly being used as an objective measure of fatigue state. It has recently been reported that autonomic nervous activity, which is expressed as total heart rate variability (HRV) power, is associated with, and can be used as an objective measure of, mental and physical fatigue. Total HRV power (log (LF + HF)) has been shown to decline with ageing, and thus cannot be utilized as a fatigue index in populations with a different age composition. In the present study, we devised standard scores (deviation value) for autonomic nervous activity corrected for individual age calculated from the distribution of such activity in individual age cohorts. This allowed us to accurately evaluate an individual's autonomic nervous activity, even when that individual was part of a group with members of different ages. Standard scores were quantified using autonomic nervous function data gathered from 1,969 healthy individuals (age range 20-77 years). The efficacy of this method in mental health screening was investigated by evaluating both autonomic nervous function and subjective levels of fatigue among corporate workers. Based on results from the Brief Job Stress Questionnaire recommended by the research team of the Ministry of Health, Labour and Welfare, 103 participants were divided into two groups (a high-stress group [n = 17] and a non-high-stress group [n = 86]). Visual analog scale (VAS) scores for all fatigue-related symptoms were significantly higher among the high-stress than among the non-high-stress group (p < 0.01). The mean standard score for autonomic nervous activity was 56.3 for the non-high-stress group. The score for the high-stress group was significantly lower, at 47.9 (p < 0.01), indicating that autonomic nervous function was reduced among participants who experienced high stress. According to an analysis of raw and standard scores in each domain, autonomic nervous activity did not significantly correlate with stress-causing factors (e.g., overwork) or other factors affecting stress responses (e.g., support from supervisors and colleagues), but did exhibit a significant positive correlation with physical and mental responses to stress (r = 0.334, p < 0.01). Lower raw scores for mental and physical responses to stress represent stronger subjective symptoms. Moreover, greater stress responses were found to be associated with lower standard scores for autonomic nervous activity. In terms of fatigue-related symptoms rated using the VAS, autonomic nervous activity negatively correlated with mental stress, physical stress, fatigue/malaise, depressed mood, anxiety/fear, tension, irritation/anger, cognitive decline, and muscle/joint/general pain, and positively correlated with motivation/vitality. Reduced autonomic nervous activity was observed with high stress, confirming that standard scores for autonomic nervous activity are associated with mental and physical responses to stress and subjective fatigue-related symptoms. These results indicate that the evaluation of autonomic nervous activity using standard scores (deviation value) is a useful tool for the objective measurement of fatigue state, even in groups with members of different ages, and can be applied as a useful objective health index to evaluate industrial fatigue.

Stress-Induced Glucocorticoid Release Upregulates Uncoupling Protein-2 Expression and Enhances Resistance to Endotoxin-Induced Lethality.

OBJECTIVE: Although psychological and/or physiological stress has been well documented to influence immune responses, the precise mechanism for immunomodulation remains to be elucidated. The present work describes the role of the hypothalamic-pituitary-adrenal (HPA) axis in the mechanism of stress-mediated enhanced-resistance to lethality after lipopolysaccharide (LPS) injection. METHODS/RESULTS: Preconditioning with restraint stress (RS) resulted in enhanced activation of the HPA axis in response to LPS injection and suppressed LPS-induced release of proinflammatory cytokines and nitric oxide metabolites. Melanocortin 2 receptor-deficient mice (MC2R(-/-)) failed to increase plasma levels of glucocorticoids in response to LPS injection, and exhibited high sensitivity to LPS-induced lethality with enhanced release of proinflammatory cytokines as compared with MC2R(+/-) mice. Real-time PCR analysis revealed that RS induced upregulation of uncoupling protein-2 (UCP2) in macrophages in the lung and the liver of MC2R(+/-), but not of MC2R(-/-), mice. In addition, RS increased UCP2-dependent uncoupling activity of isolated mitochondria from the liver of MC2R(+/-), but not of MC2R(-/-), mice. In vitro study revealed that corticosterone and dexamethasone directly increased UCP2 expression in mouse RAW 264.7 macrophages and suppressed the generation of LPS-induced mitochondrial reactive oxygen species (ROS) and TNF-α production. Knockdown of UCP2 by small interfering RNA blunted the dexamethasone action for suppressing LPS-induced mitochondrial ROS and TNF-α production. CONCLUSION: The present work suggests that RS enhances activation of the HPA axis to release glucocorticoids and upregulation of UCP2 in macrophages, thereby increasing the resistance to endotoxin-induced systemic inflammation and death.

Dynamic aspects of ascorbic acid metabolism in the circulation: analysis by ascorbate oxidase with a prolonged in vivo half-life.

Because AA (L-ascorbic acid) scavenges various types of free radicals to form MDAA (monodehydroascorbic acid) and DAA (dehydroascorbic acid), its regeneration from the oxidized metabolites is critically important for humans and other animals that lack the ability to synthesize this antioxidant. To study the dynamic aspects of AA metabolism in the circulation, a long acting AOase (ascorbate oxidase) derivative was synthesized by covalently linking PEG [poly(ethylene glycol)] to the enzyme. Fairly low concentrations of the modified enzyme (PEG-AOase) rapidly decreased AA levels in isolated fresh plasma and blood samples with a concomitant increase in their levels of MDAA and DAA. In contrast, relatively high doses of PEG-AOase were required to decrease the circulating plasma AA levels of both normal rats and ODS (osteogenic disorder Shionogi) rats that lack the ability to synthesize AA. Administration of 50 units of PEG-AOase/kg of body weight rapidly decreased AA levels in plasma and the kidney without affecting the levels in other tissues, such as the liver, brain, lung, adrenal grand and skeletal muscles. PEG-AOase slightly, but significantly, decreased glutathione (GSH) levels in the liver without affecting those in other tissues. Suppression of hepatic synthesis of GSH by administration of BSO [L-buthionin-(S,R)-sulfoximine] enhanced the PEG-AOase-induced decrease in plasma AA levels. These and other results suggest that the circulating AA is reductively regenerated from MDAA extremely rapidly and that hepatic GSH plays important roles in the regeneration of this antioxidant.