stress – Page 3 – American ME and CFS Society

The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients

Abstract:

BACKGROUND: Despite extensive research, no reliable biological marker for chronic fatigue syndrome (CFS) has yet been identified. However, hyperactivation of melanotrophs in the pituitary gland and increased levels of plasma alpha-melanocyte-stimulating hormone (alpha-MSH) have recently been detected in an animal model of chronic stress. Because CFS is considered to be caused partly by chronic stress events, increased alpha-MSH plasma levels may also occur in CFS patients. We therefore examined alpha-MSH levels in CFS patients.

METHODS: Fifty-five CFS patients, who were previously diagnosed within 10 years of with the disease, were enrolled in this study. Thirty healthy volunteers were studied as controls. Fasting bloods samples were collected in the morning and evaluated for their plasma levels of alpha-MSH, adrenocorticotropic hormone (ACTH), serum cortisol and dehydroepiandrosterone sulfate (DHEA-S). Mean levels of alpha-MSH were compared between the CFS and control groups using Welch’s t test.

RESULTS: The mean plasma alpha-MSH concentration in the CFS group (17.9 +/- 1.0 pg/mL) was significantly higher than that in healthy controls (14.5 +/- 1.0 pg/mL, p = 0.02). However, there was a wide range of values in the CFS group. The factors correlated with the plasma alpha-MSH values were analyzed using Spearman’s rank correlation. A negative correlation was found between the duration of the CFS and the plasma alpha-MSH values (p = 0.04, rs = -0.28), but no correlations with ACTH, cortisol or DHEA-S levels were identified (p = 0.55, 0.26, 0.33, respectively). The CFS patients were divided into two groups: patients diagnosed for <or= 5 years’ duration, and those diagnosed for 5-10 years’ duration. They were compared with the healthy controls using one-way ANOVA and Tukey-Kramer multiple comparison tests. The mean alpha-MSH concentration in the <or= 5 years group was 20.8 +/- 1.2 pg/mL, which was significantly higher than that in the healthy controls (p < 0.01). There was no significant difference between the 5-10 year group (15.6 +/- 1.4 pg/mL) and the healthy controls.

CONCLUSIONS:CFS patients with a disease duration of <or= 5 years had significantly higher levels of alpha-MSH in their peripheral blood. alpha-MSH could be a potent biological marker for the diagnosis of CFS, at least during the first 5 years after onset of the disease.

Source: Shishioh-Ikejima N, Ogawa T, Yamaguti K, Watanabe Y, Kuratsune H, Kiyama H. The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients. BMC Neurol. 2010 Aug 23;10:73. doi: 10.1186/1471-2377-10-73. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933583/ (Full article)

Neuroendocrine and immune contributors to fatigue

Abstract:

Central fatigue, a persistent and subjective sense of tiredness, generally correlates poorly with traditional markers of disease. It is frequently associated with psychosocial factors, such as depression, sleep disorder, anxiety, and coping style, which suggest that dysregulation of the body’s stress systems may serve as an underlying mechanism in the maintenance of chronic fatigue (CF).

This article addresses the endocrine, neural, and immune factors that contribute to fatigue and describes research regarding the role of these factors in chronic fatigue syndrome as a model for addressing the biology of CF. In general, hypoactivity of the hypothalamic-pituitary-adrenal axis, autonomic nervous system alterations characterized by sympathetic overactivity and low vagal tone, as well as immune abnormalities, may contribute to the expression of CF. Noninvasive methods for evaluating endocrine, neural, and immune function are also discussed.

Simultaneous evaluation of neuroendocrine and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems, their role in disease susceptibility, and progression of stress-related disorders.

Source: Silverman MN, Heim CM, Nater UM, Marques AH, Sternberg EM. Neuroendocrine and immune contributors to fatigue. PM R. 2010 May;2(5):338-46. doi: 10.1016/j.pmrj.2010.04.008. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933136/ (Full article)

Assessment of Cellular Bioenergetics in Chronic Fatigue Syndrome

Introduction: Abnormalities in bioenergetic function have been cited as one possible cause for chronic fatigue syndrome (CFS). One hypothesis to explain this suggests that CFS may be caused, at least in part, by an acquired mitochondrial dysfunction.

Extracellular flux analysers make real-time, in vitro assessment of cellular energy pathways possible. Using this technology, mitochondrial function can be measured in a variety of cell types in real-time thus increasing our understanding of the role of metabolism in CFS.

Objectives: This project aims to utilise extracellular flux detection technology in order to investigate the cellular bioenergetics of different cell types obtained from CFS patients and healthy controls.

Methods: Mitochondrial stress tests were conducted using skeletal muscle cells and peripheral blood mononuclear cells (PBMCs) derived from CFS patients and controls. During this test mitochondrial complexes are inhibited in turn to modulate respiration so mitochondrial function can be evaluated. The oxygen consumption rate of cells is measured which allows keys parameters of mitochondrial function to be measured and calculated in a single experiment, providing an overall assessment of mitochondrial function. Parameters measured are: basal respiration, maximal respiration and non-mitochondrial respiration. Proton leak, ATP-production and spare respiratory capacity are subsequently able to be calculated using the three measured parameters. CFS patients whose samples were used in these studies were diagnosed using the Fukuda definition.

Results: Results using skeletal muscle cells obtained from CFS patients (n=3) and controls (n=5), indicate that there is no difference in the energy profiles of the skeletal muscle cells of CFS patients in any of the parameters investigated.

Mitochondrial stress test results using PBMCs show CFS PBMCs (n=7) to be significantly lower than control cells (n=10) in all parameters investigated (p≤0.016). Importantly, these results suggest that CFS PBMCs perform closer to their maximum under normal conditions. This means that when CFS PBMCs come under stress they are less able to increase their respiration rate to compensate for the increase in stress.

Conclusions: These findings provide an interesting starting point for investigations into cellular bioenergetics in CFS.

Cara Jasmine Tomas; First year medical science PhD student; Institute of Cellular Medicine, Level 1, William Leech Building, Medical School, Newcastle University, Newcastle Upon-Tyne, NE2 4HH, England; c.j.tomas@ncl.ac.uk
This work was funded by the Medical Research Council and Newcastle University.

Source: Cara Tomas, Julia Newton, Audrey Brown, Gina Rutherford, Philip Manning
Newcastle University, UK. Assessment of Cellular Bioenergetics in Chronic Fatigue Syndrome. Poster presentation, IACFS/ME 2016 conference.

Chronic fatigue syndrome and high allostatic load: results from a population-based case-control study in Georgia

Abstract:

OBJECTIVE: To confirm the association of chronic fatigue syndrome (CFS) with high allostatic load (AL) level, examine the association of subsyndromal CFS with AL level, and investigate the effect of depression on these relationships and the association of AL with functional impairment, fatigue, symptom severity, fatigue duration, and type of CFS onset. AL represents the cumulative physiologic effect of demands to adapt to stress.

METHODS: Population-based case-control study of 83 persons with CFS, 202 persons with insufficient symptoms or fatigue for CFS (ISF), and 109 well controls living in Georgia. Unconditional logistic regression was used to generate odds ratios (ORs) as measures of the association of AL with CFS.

RESULTS: Relative to well controls, each 1-point increase in allostatic load index (ALI) was associated with a 26% increase in likelihood of having CFS (OR(adjusted) = 1.26, 95% Confidence Interval (CI) = 1.00, 1.59). This association remained in the presence and absence of depression (OR(adjusted) = 1.35, CI = 1.07, 1.72; OR(adjusted) = 1.35, CI = 1.10, 1.65). Compared with the ISF group, each 1-point increase in ALI was associated with a 10% increase in likelihood of having CFS (OR(adjusted) = 1.10, CI = 0.93, 1.31). Among persons with CFS, the duration of fatigue was inversely correlated with ALI (r = -.26, p = .047).

CONCLUSIONS: Compared with well controls, persons with CFS were significantly more likely to have a high AL. AL increased in a gradient across well, ISF, and CFS groups.

Source: Maloney EM, Boneva R, Nater UM, Reeves WC. Chronic fatigue syndrome and high allostatic load: results from a population-based case-control study in Georgia. Psychosom Med. 2009 Jun;71(5):549-56. doi: 10.1097/PSY.0b013e3181a4fea8. Epub 2009 May 4. https://www.ncbi.nlm.nih.gov/pubmed/19414615 (Full article)

Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a ‘crash’ in the stress system?

Abstract:

The etiopathogenesis of chronic fatigue syndrome (CFS) remains poorly understood. Although neuroendocrine disturbances – and hypothalamic-pituitary-adrenal (HPA) axis hypofunction in particular – have been found in a large proportion of CFS patients, it is not clear whether these disturbances are cause or consequence of the illness.

After a review of the available evidence we hypothesize that that HPA axis hypofunction in CFS, conceptualized within a system-biological perspective, primarily reflects a fundamental and persistent dysregulation of the neurobiological stress system. As a result, a disturbed balance between glucocorticoid and inflammatory signaling pathways may give rise to a pathological cytokine-induced sickness response that may be the final common pathway underlying central CFS symptoms, i.e. effort/stress intolerance and pain hypersensitivity.

This comprehensive hypothesis on HPA axis hypofunction in CFS may stimulate diagnostic refinement of the illness, inform treatment approaches and suggest directions for future research, particularly focusing on the neuroendocrine-immune interface and possible links between CFS, early and recent life stress, and depression.

Source: Van Houdenhove B, Van Den Eede F, Luyten P. Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a ‘crash’ in the stress system? Med Hypotheses. 2009 Jun;72(6):701-5. doi: 10.1016/j.mehy.2008.11.044. Epub 2009 Feb 23. https://www.ncbi.nlm.nih.gov/pubmed/19237251

Can sustained arousal explain the Chronic Fatigue Syndrome?

Abstract:

We present an integrative model of disease mechanisms in the Chronic Fatigue Syndrome (CFS), unifying empirical findings from different research traditions. Based upon the Cognitive activation theory of stress (CATS), we argue that new data on cardiovascular and thermoregulatory regulation indicate a state of permanent arousal responses – sustained arousal – in this condition.

We suggest that sustained arousal can originate from different precipitating factors (infections, psychosocial challenges) interacting with predisposing factors (genetic traits, personality) and learned expectancies (classical and operant conditioning).

Furthermore, sustained arousal may explain documented alterations by establishing vicious circles within immunology (Th2 (humoral) vs Th1 (cellular) predominance), endocrinology (attenuated HPA axis), skeletal muscle function (attenuated cortical activation, increased oxidative stress) and cognition (impaired memory and information processing). Finally, we propose a causal link between sustained arousal and the experience of fatigue.

The model of sustained arousal embraces all main findings concerning CFS disease mechanisms within one theoretical framework.

Source: Wyller VB, Eriksen HR, Malterud K. Can sustained arousal explain the Chronic Fatigue Syndrome? Behav Brain Funct. 2009 Feb 23;5:10. doi: 10.1186/1744-9081-5-10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654901/ (Full article)

Hyperventilation in patients with chronic fatigue syndrome: the role of coping strategies

Abstract:

Hyperventilation has been suggested as a concomitant and possible maintaining factor that may contribute to the symptom pattern of chronic fatigue syndrome (CFS). Because patients accepting the illness and trying to live with it seem to have a better prognosis than patients chronically fighting it, we investigated breathing behavior during different coping response sets towards the illness in patients with CFS (N=30, CDC criteria).

Patients imagined a relaxation script (baseline), a script describing a coping response of hostile resistance, and a script depicting acceptance of the illness and its (future) consequences. During each imagery trial, end-tidal PCO2 (Handheld Capnograph, Oridion) was measured. After each trial, patients filled out a symptom checklist. Results showed low resting values of PetCO2 overall, while only imagery of hostile resistance triggered a decrease and deficient recovery of PetCO2. Also, more hyperventilation complaints and complaints of other origin were reported during hostile resistance imagery compared with acceptance and relaxation.

In conclusion, hostile resistance seems to trigger both physiological and symptom perception processes contributing to the clinical picture of CFS.

Source: Bogaerts K, Hubin M, Van Diest I, De Peuter S, Van Houdenhove B, Van Wambeke P, Crombez G, Van den Bergh O. Hyperventilation in patients with chronic fatigue syndrome: the role of coping strategies. Behav Res Ther. 2007 Nov;45(11):2679-90. Epub 2007 Jul 20. https://www.ncbi.nlm.nih.gov/pubmed/17719001

Premorbid predictors of chronic fatigue

Abstract:

CONTEXT: Chronic fatigue syndrome is a disabling problem characterized by persistent fatigue lasting at least 6 months with a number of ancillary symptoms. Although the etiology of chronic fatiguing illness is unknown, some evidence suggests that stress may confer increased risk for development of the disorder. Moreover, subjects with chronic fatiguing illness may have distinctive personality traits, although this finding could reflect confounding by other mechanisms.

OBJECTIVE: To assess the prospective association of premorbid self-reported stress and personality with chronic fatigue-like illness.

DESIGN: Prospective nested case-control study in a population-based sample.

SETTING: General community.

PARTICIPANTS: From the Swedish Twin Registry, 19,192 twins born between January 1, 1935, and December 31, 1958.

MAIN OUTCOME MEASURES: Information about current chronic fatiguing illnesses was obtained from computer-assisted telephone interviews conducted between 1998 and 2002. Self-reported stress (based on a single question) and personality scales (emotional instability and extraversion in the Eysenck Personality Inventory) were measured from 1972 to 1973 by a mailed questionnaire. Relative risks were estimated with case-control analyses (matched for age and sex) and co-twin control analyses (comparing discordant pairs).

RESULTS: Higher emotional instability and self-reported stress in the premorbid period were associated with higher risk for chronic fatigue-like illness in matched case-control analyses (odds ratios, 1.72 and 1.64, respectively). In co-twin control analyses, relative risk of emotional instability decreased to 1.02 whereas that of stress increased considerably to 5.81. There was no association between extraversion and fatigue.

CONCLUSIONS: Elevated premorbid stress is a significant risk factor for chronic fatigue-like illness, the effect of which may be buffered by genetic influences. Emotional instability assessed 25 years earlier is associated with chronic fatigue through genetic mechanisms contributing to both personality style and expression of the disorder. These findings suggest plausible mechanisms for chronic fatiguing illness.

Source: Kato K, Sullivan PF, Evengård B, Pedersen NL. Premorbid predictors of chronic fatigue. Arch Gen Psychiatry. 2006 Nov;63(11):1267-72. https://www.ncbi.nlm.nih.gov/pubmed/17088507

Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome

Abstract:

OBJECTIVE: It has been suggested that a hypofunctional hypothalamic-pituitary-adrenal (HPA) axis in chronic fatigue syndrome could result in an exaggerated release of pro-inflammatory cytokines during stress. As pro-inflammatory cytokines are involved in the induction of sickness behavior and thus constitute a potential physiological correlate of stress-induced symptom exacerbation in chronic fatigue syndrome, we set out to evaluate the LPS-induced production of pro-inflammatory cytokines during psychosocial stress in CFS and healthy controls.

METHOD: Twenty-one CFS patients and 20 healthy controls matched for age and gender underwent a standardized psychosocial stress test (Trier social stress test, TSST). Adrenocorticotropine hormone (ACTH), salivary cortisol and plasma cortisol levels were measured before and repeatedly following exposure to the stressor. Lipopolysaccharide-stimulated production of interleukin-6 and tumor necrosis factor-alpha were assessed at baseline as well as 10 and 60 min after the stress test.

RESULTS: CFS patients showed an inverse stress-induced response pattern of LPS-stimulated cytokines responses in comparison to healthy controls, i.e. stimulated cytokine production decreased shortly after stress in CFS patients, while it increased in controls. Fatigue scores and basal LPS-induced cytokine levels were significantly associated for TNF-alpha in controls and for both cytokines in CFS patients. Stress-induced changes in stimulated cytokine production were not associated with general fatigue scores in the control group, whereas in the CFS group, fatigue scores were significantly correlated with integrated levels of LPS-induced cytokines. However, partial correlations revealed that these results were due to the high correlations with basal LPS-induced cytokine levels.

CONCLUSION: CFS patients do not show an exaggerated secretion of LPS-induced cytokines. Although cortisol responses to stress were normal, pro-inflammatory cytokine levels in CFS patients were significantly attenuated. Possible intracellular mechanisms, such as for example an enhanced sensitivity to inhibitory effects of glucocorticoids, a diminished responsivity to catecholaminergic stimulation, and a disruption of intracellular activation are discussed. Basal levels of stimulated pro-inflammatory Il-6 levels are generally related to fatigue scores. However, in CFS patients this association is of greater magnitude and can also be observed for TNF-alpha.

Source: Gaab J, Rohleder N, Heitz V, Engert V, Schad T, Schürmeyer TH, Ehlert U. Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome. Psychoneuroendocrinology. 2005 Feb;30(2):188-98. http://www.ncbi.nlm.nih.gov/pubmed/15471616

Regional prevalence of fatiguing illnesses in the United States before and after the terrorist attacks of September 11, 2001

Abstract:

OBJECTIVE: Stress or emotional traumas are considered risk factors for unexplained fatiguing illnesses. From July to December 2001, the Centers for Disease Control and Prevention conducted a multigeographical pilot study to test the feasibility of a survey to estimate the prevalence of fatiguing illnesses in the United States. We used data obtained during this survey to estimate the effect of the coincidentally occurring terrorist attacks of September 11, 2001, on the regional prevalence of fatiguing illnesses.

METHODS: Identified by random-digit dialing, 2,728 households in eight regional strata were interviewed, and 7,317 respondents were screened for severe fatigue of at least 1 month duration. Identified fatigued people of age 18 to 69 years (N = 440) and a sample of nonfatigued people of the same age range (N = 444) were interviewed in detail concerning fatigue, other symptoms, and medical and psychiatric histories.

RESULTS: Weighted prevalence estimates based on interviews performed after the attacks were significantly lower compared with estimates based on interviews performed before the attacks (prolonged fatigue: 5,450 vs. 1,530/100,000, p =.010; chronic fatigue: 18,510 vs. 10,070/100,000, p =.002; chronic fatigue syndrome-like illness: 2,510 vs. 960/100,000, p =.014).

CONCLUSION: Our findings suggest decreased regional prevalence of fatiguing illnesses in the aftermath of the terrorist attacks. The causes of this effect are unknown but might involve acute psychological and physiological adaptations that modify the perception or manifestation of fatigue. Future studies should be specifically designed to scrutinize the relationship between stress and fatiguing illnesses and the mediating mechanisms of such a relationship.

Source: Heim C, Bierl C, Nisenbaum R, Wagner D, Reeves WC. Regional prevalence of fatiguing illnesses in the United States before and after the terrorist attacks of September 11, 2001. Psychosom Med. 2004 Sep-Oct;66(5):672-8. http://www.ncbi.nlm.nih.gov/pubmed/15385690