Long-term stress exposure, cortisol level and cardiovascular activity and reactivity: Observations in patients with fibromyalgia.

Previous research suggested that exposure to long-lasting or repeated laboratory stressors may lead to rearrangement of cardiovascular control, with a shift of regulation mechanisms from dominant cardiac to dominant vascular influences between the early and late response phases, respectively. This study investigated whether similar rearrangement occurs during life stress accompanying chronic disease by analyzing also associations between cortisol level and cardiovascular variables in patients with fibromyalgia (FM). In 47 women with FM and 36 healthy women (HW), cardiovascular recordings were taken during active body posture changes (sitting, lying down, and standing). Moreover, hair cortisol concentration (HCC) was obtained. During standing, which involved orthostatic challenge, FM patients showed higher total peripheral resistance (TPR) but lower stroke volume (SV), cardiac output (CO), and baroreflex sensitivity than HW. During sitting and lying down, TPR was more closely associated with blood pressure (BP) than CO in FM patients; in contrast, CO was more closely associated with BP than TPR in HW. HCC correlated positively with TPR and BP in FM patients, but negatively with TPR and BP and positively with SV and CO in HW. Results suggest that chronic disease-related stress is associated with alterations in cardiovascular regulation toward greater involvement of vascular than cardiac mechanisms in BP control. Stress-related cortisol release may contribute to the long-term rearrangement of autonomic regulation. At the behavioral level, the dominance of vascular over cardiovascular control may relate to reduced somatic mobilization during an active fight-flight response in favor of passive and behaviorally immobile coping.

Impact of homeostatic body hydration status, evaluated by hemodynamic measures, on different pain sensitization paths to a chronic pain syndrome.

Contrasting findings on the mechanisms of chronic pain and hypertension development render the current conventional evidence of a negative relationship between blood pressure (BP) and pain severity insufficient for developing personalized treatments. In this interdisciplinary study, patients with fibromyalgia (FM) exhibiting clinically normal or elevated BP, alongside healthy participants were assessed. Different pain sensitization responses were evaluated using a dynamic 'slowly repeated evoked pain' (SREP) measure, as well as static pain pressure threshold and tolerance measures. Cardiovascular responses to clino-orthostatic (lying-standing) challenges were also examined as acute re- and de-hydration events, challenging cardiovascular and cerebrovascular homeostasis. These challenges involve compensating effects from various cardiac preload or afterload mechanisms associated with different homeostatic body hydration statuses. Additionally, hair cortisol concentration was considered as a factor with an impact on chronic hydration statuses. Pain windup (SREP) and lower pain threshold in FM patients were found to be related to BP rise during clinostatic (lying) rehydration or orthostatic (standing) dehydration events, respectively. These events were determined by acute systemic vasoconstriction (i.e., cardiac afterload response) overcompensating for clinostatic or orthostatic cardiac preload under-responses (low cardiac output or stroke volume). Lower pain tolerance was associated with tonic blood pressure reduction, determined by permanent hypovolemia (low stroke volume) decompensated by permanent systemic vasodilation. In conclusion, the body hydration status profiles assessed by (re)activity of systemic vascular resistance and effective blood volume-related measures can help predict the risk and intensity of different pain sensitization components in chronic pain syndrome, facilitating a more personalized management approach.

Alexithymia is associated with an augmenter profile, but not only: evidence for anticipation to arousing music.

It has been suggested that high alexithymia scorers have an 'augmenter' profile which amplifies their physiological and subjective responses to highly arousing stimuli. The aim of this study was to test this theory using several physiological measures. Participants listened to musical excerpts either in a 'weak-to-strong' or a 'strong-to-weak' order of arousing levels of stimuli. The results show that alexithymia was associated with an augmenter profile for subjective reports for the most arousing stimulus and with stronger skin conductance level responses in the 'strong-to-weak' order. These results partially support the augmenter profile and reveal that alexithymia may be associated with higher anticipation for the most arousing excerpt.

Blunted short-term autonomic cardiovascular reactivity to orthostatic and clinostatic challenges in fibromyalgia as an indicator of the severity of chronic pain.

Fibromyalgia is a long-term pain disorder that has been related to autonomic dysfunctions and reduced cardiovascular reactivity. We aimed to assess the dynamic short-term cardiovascular responses to postural changes in fibromyalgia. Thirty-eight women with fibromyalgia and thirty-six healthy women underwent the "Chronic Pain Autonomic Stress Test". Electrocardiogram, blood pressure and impedance cardiography were continuously recorded during active standing and lying down. Second-by-second values were derived over the first 30 s of each posture. Lower reactivity during the beginning of each position was observed in fibromyalgia sufferers compared to healthy women, with smaller responses seen during stand up in heart rate, blood pressure, cardiac output, total peripheral resistance, and pre-ejection period, and smaller changes during lying down in heart rate, cardiac output and total peripheral resistance. The magnitude of the autonomic adjustments to postural changes was inversely associated with the severity of clinical pain. These findings indicate an early impaired autonomic cardiovascular response to orthostatic and clinostatic challenges in fibromyalgia, suggesting less autonomic flexibility and adaptability to situational demands and challenges. Short-term second-by-second cardiovascular measures may be useful in the clinical assessment of fibromyalgia.

Making the choice between bioelectrical impedance measures for body hydration status assessment.

Situational or persistent body fluid deficit (i.e., de- or hypo-hydration) is considered a significant health risk factor. Bioimpedance analysis (BIA) has been suggested as an alternative to less reliable subjective and biochemical indicators of hydration status. The present study aimed to compare various BIA models in the prediction of direct measures of body compartments associated with hydration/osmolality. Fish (n = 20) was selected as a biological model for physicochemically measuring proximate body compartments associated with hydration such as water, dissolved proteins, and non-osseous minerals as the references or criterion points. Whole-body and segmental/local impedance measures were used to investigate a pool of BIA models, which were compared by Akaike Information Criterion in their ability to accurately predict the body components. Statistical models showed that 'volumetric-based' BIA measures obtained in parallel, such as distance2/Rp, could be the best approach in predicting percent of body moisture, proteins, and minerals in the whole-body schema. However, serially-obtained BIA measures, such as the ratio of the reactance to resistance and the resistance adjusted for distance between electrodes, were the best fitting in predicting the compartments in the segmental schema. Validity of these results should be confirmed on humans before implementation in practice.

Personalized behavior management as a replacement for medications for pain control and mood regulation.

A lack of personalized approaches in non-medication pain management has prevented these alternative forms of treatment from achieving the desired efficacy. One hundred and ten female patients with fibromyalgia syndrome (FMS) and 60 healthy women without chronic pain were assessed for severity of chronic or retrospective occasional pain, respectively, along with alexithymia, depression, anxiety, coping strategies, and personality traits. All analyses were conducted following a 'resource matching' hypothesis predicting that to be effective, a behavioral coping mechanism diverting or producing cognitive resources should correspond to particular mechanisms regulating pain severity in the patient. Moderated mediation analysis found that extraverts could effectively cope with chronic pain and avoid the use of medications for pain and mood management by lowering depressive symptoms through the use of distraction mechanism as a habitual ('out-of-touch-with-reality') behavior. However, introverts could effectively cope with chronic pain and avoid the use of medications by lowering catastrophizing through the use of distraction mechanism as a situational ('in-touch-with-reality') behavior. Thus, personalized behavior management techniques applied according to a mechanism of capturing or diverting the main individual 'resource' of the pain experience from its 'feeding' to supporting another activity may increase efficacy in the reduction of pain severity along with decreasing the need for pain relief and mood-stabilizing medications.

Impact of antihypertensive treatment on resiliency to clinical pain.

OBJECTIVES: Although progress has been made in the regulation of hypertension over the past decades, the USA and some other countries have faced a significant rise in incidence of chronic pain management cases during the same period. Studies of the relationship between pain and blood pressure (BP) regulations propose that these two processes may be interconnected. Studies of effects of antihypertensive treatment on pain in general and its chronification have never been reviewed. METHODS: A narrative review of respective studies with analysis of credibility of the findings was conducted. RESULTS: Some studies have suggested that aggressive reduction of high BP may contribute to a return in pain symptoms and may require more aggressive, long-term pain management. Other studies propose that long-term antihypertensive medication could also increase the risk for new cases of chronic pain. Pain initiates a central neuroplastic resetting of the baroreceptor activation accounting for sustained increase of BP with an adaptive 'pain-killing' or maladaptive 'pain-complication' effect associated with pain chronification, and these mechanisms may be moderated by antihypertensive medications. However, different antihypertensive drugs and nondrug treatments may diversely affect pain mechanisms at different stages of treatments. CONCLUSION: Uncontrollable reduction of high BP in some patients with hypertension could increase the risk for chronic pain incidence and its severity. Practical recommendations in BP control should be reconsidered to take into account patients' chronic pain. Further research is needed of moderation effects of different antihypertensive manipulations on pain to improve pain management in these patients.

Cardiovascular phenotyping for personalized lifestyle treatments of chronic abdominal pain in Irritable Bowel Syndrome: A randomized pilot study.

BACKGROUND: Different physical exercise interventions for pain and other related symptoms largely follow non-personalized guidelines and show a high degree of variability in outcome. These interventions are considered to have different pathways toward improvement in autonomic regulation of energy metabolism. The current pilot study was conducted to assess the predictive value of individual cardiovascular (CV) activity markers at rest to predict clinical outcomes for two popular exercise-based interventions (walking and yoga) in patients with Irritable Bowel Syndrome (IBS). METHODS: Twenty-seven adult participants with IBS were randomly assigned to a 16-biweekly Iyengar yoga or walking program. They completed pre- and post-treatment assessments on IBS symptom severity, affective and somatic complaints, and various measures of resting autonomic function including blood pressure (BP), heart rate and its variability, baroreceptor sensitivity (BRS) to activations and inhibitions with gains of brady- and tachycardiac baro-responses, and BP start points for these spontaneous baroreflexes. RESULTS: Pretreatment BRS was differentially related to clinical response for the treatment groups. Specifically, a significant decrease in pain severity was found in response to yoga for those participants who had lower resting BRS to activations, but decreased pain severity was associated with higher resting BRS for those in the walking group. The effect was not related to affective symptom relief. Other CV measures showed similar associations with clinical outcomes for both groups. CONCLUSIONS: The data suggest therefore that CV based phenotypes may be useful in personalizing clinical interventions for IBS. They may also point to autonomic mechanisms that are targets for such interventions.

Baroreflex mechanisms in major depression.

BACKGROUND: Recent studies have shown that depressive disorder is associated with impaired baroreceptor or baroreflex sensitivity, which is proposed to be a predisposing factor for sudden death in patients with manifest cardiac disease. These studies have not evaluated the afferent and efferent components of the cardiac baroreflex loop or other baroreflex mechanisms that regulate target processes (cardiac metabolism and blood pressure variability) related to the impairment. The objective of this study was to gain more insight into autonomic functioning in depressive disorder to more fully examine the potential basis for increased cardiac mortality. METHODS: The subjects were 28 women and men with unipolar major depression who were taking antidepressant medications and who were in partial remission and free of cardiovascular or other serious disease, and 28 healthy control subjects matched for sex, age, and ethnicity. The two samples were compared for negative affective dispositions (anger expression, hostility, defensiveness, anxiety), spontaneous (closed-loop) baroreflex activity, heart rate, heart rate variability, systolic blood pressure, and heart rate-systolic blood pressure double product under resting conditions. RESULTS: Depressed patients showed a general disposition to anger suppression coupled with higher hostility and anxiety, and lower defensiveness. The patients showed higher general sympathetic activity (high levels of blood pressure, low-frequency heart rate variability) and lower parasympathetic-related activity (high heart rate and reduced high frequency heart rate variability) with affected cardiac metabolism estimated by the double product. Depressed patients had lower baroreflex sensitivity related to a higher gain of the afferent component of the baroreflex without respective gain adjustment of its efferent component (reflex gain 'de-afferentation'). It was coupled with a compensatory higher number of effective baroreflex reactions (reflex gating 're-afferentation'). Antidepressant agents and depressed mood had additional independent effects on baroreflex sensitivity through the efferent component of the cardiac baroreflex loop. CONCLUSIONS: The data indicate that different baroreflex components and mechanisms may be impaired in patients with depression and may contribute to their increased cardiac risk.

Moods in everyday situations: effects of combinations of different arousal-related factors.

OBJECTIVE: This study examined women's mood responsiveness associated with patterns of stress hormone levels in everyday situations. METHODS: Self-reports of negative, positive, and energy dimensions of mood were obtained from 203 nurses throughout the day on a workday and on an off-work day during the luteal and follicular phases of the menstrual cycle. Individual differences in daytime norepinephrine and cortisol were assessed. RESULTS: Patterns of norepinephrine and cortisol levels were associated with ratings of the following moods: tired, sad, and happy. Phase of the menstrual cycle and the day factor (workday, off-work day) modified the association of mood ratings and stress hormone patterns. CONCLUSION: The experience of negative mood is associated with both hypoarousal and hyperarousal conditions. A homeostatic arousal-related concept of mood regulation is discussed.

Orthostatic cardiovascular profile of subjective well-being.

Previous clinical and elderly population studies have found that affective well-being can be assessed by clino-orthostatic cardiovascular reactivity. This study explored this relationship in a young healthy sample, and with respect to cognitive appraisals of well-being. Four successive readings of blood pressure (BP) and heart rate (HR) after lying down (clinostatic probe) followed by four successive readings after standing up (orthostatic probe) were obtained from 52 healthy students along with questionnaire-reported well-being. Analyses indicated that a deeper drop of systolic BP (SBP) and mean arterial (MAP) pressure during supine was related to higher positive mood, but higher and more stable orthostatic MAP and HR response were related to lower negative mood. A higher diastolic BP while standing upright and lower SBP in general were associated with higher optimism and higher global life satisfaction, respectively. The findings confirm previous results and indicate that cognitive appraisals of well-being are also related to BP regulation.

Central and peripheral pathogenetic forms of type 2 diabetes: a proof-of-concept study.

HYPOTHESIS: Previous studies provide evidence that glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) should not be considered as interchangeable alternatives in the diagnosis of the same type 2 diabetes, but as indicators of its different pathogenetic subtypes. This study was conducted to determine whether a particularly high amount of glucose in either HbA1c form or in fasting plasma would be found in diabetic patients genetically predisposed for either intensive cognitive or intensive muscle metabolic activity, respectively. METHODS: HbA1c and FPG levels, polymorphisms of genes indicating the predisposition to different cognitive activity (the dopamine D2 receptor (DRD2/ANKK1)), muscle activity (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1A(PPARGC1A))), and vascular regulation of general metabolic activity (the angiotensin 1 converting enzyme (ACE)) were assessed in diabetic patients and nondiabetic controls. RESULTS: DRD2/ANKK1 polymorphism that affects baseline central arousal determined HbA1c variations uncorrelated with FPG in total and clinical groups. The mutation of PGC1A mainly affecting peripheral glucose metabolism had an effect on FPG correlated or uncorrelated with HbA1c depending on the effect assessment in the total sample or in the nondiabetic group, respectively. ACE insertion/deletion (I/D) gene polymorphism was associated with both HbA1c and FPG fluctuations, but only in diabetic patients. CONCLUSION: The findings provide evidence that the HbA1c and FPG may predict the risks for different subtypes of type 2 diabetes associated with either brain or muscle metabolic activity in genetically vulnerable people.

Baroreflex mechanisms in Irritable Bowel Syndrome: Part I. Traditional indices.

OBJECTIVE: This study was conducted to present evidence of differences in autonomic regulation of cardiovascular activity and its role in the severity of specific (disease-related) and non-specific (negative affect and chronic pain-related) symptoms in individuals with Irritable Bowel Syndrome (IBS). METHODS: Seventy-eight female patients with IBS and 27 healthy women age 18-62 years were assessed for IBS symptoms, negative affect, and baroreceptor sensitivity (BRS), blood pressure (BP), heart rate, and heart rate variability (HRV) at rest. Direct and indirect regression effects were examined with application of the bootstrap procedure to validate findings. RESULTS: IBS was reliably related to lower resting BRS, higher BP, and higher negative affect compared to healthy controls. Longer disease duration (chronicity) was related to BRS decrease coupled with systolic BP increase (95% CIs=-0.14 to -0.01). Three autonomic mechanisms associated with BRS decrease were found to further regulate severity of IBS symptoms. Lower BRS was related to higher IBS severity in general if the effect was transferred through the decrease of low frequency power of HRV (e.g., 95% CIs=-0.039 to -0.001 for abdominal pain severity). However, lower BRS was related to lower IBS severity in general if the effect was transferred through diastolic BP increase (95% CIs=0.01-0.11 for abdominal pain severity). Lower BRS was related to higher abdominal pain severity coupled with high negative affect if the effect was transferred through the decrease of higher frequency power of HRV (95% CIs=-0.026 to -0.003). CONCLUSIONS: These findings indicate that different cardiovascular mechanisms are associated with IBS development and the increase and decrease of severity of IBS symptoms. Their assessment suggests ways to personalize treatment of IBS.

Moods in everyday situations: effects of menstrual cycle, work, and stress hormones.

OBJECTIVE: This study examined women's mood responsiveness on work and off days during different phases of the menstrual cycle. METHODS: Self-reports of negative, positive, and energy dimensions of mood were obtained throughout the day on two work and two off days during the luteal and follicular phases of the menstrual cycle in 203 women nurses. Individual differences in daytime and nighttime epinephrine, norepinephrine, and cortisol were assessed. RESULTS: High daytime norepinephrine, epinephrine, and cortisol levels were associated with higher ratings of stress and tired, and with lower ratings of happy. The phase of the menstrual cycle and the day factor (workday, off day) were also associated with mood differences, and the direction of the effects depended on hormone levels and hormone sampling period. CONCLUSION: The experience of moods is affected by the arousal-related interaction of hormone levels with the phase of the menstrual cycle and occupational stress.

Cardiovascular activity and chronic pain severity.

OBJECTIVE: Objective markers of chronic pain severity are needed when examining and treating patients with chronic pain whose suffering may be overstated or underestimated. This study tested a hypothesis that the strength of cardiovascular (CV) reactivity in response to a social evaluative threat and orthostatic challenge is a reliable index of severity of pain-related complaints. METHODS: Measurement of CV reactivity and response styles in 34 men and 16 women with chronic pain from different bodily injuries, were retrieved from a larger database of patients. Measurement of CV reactivity in response to a postural challenge was repeated twice (sessions 1 and 2) on the same day of a medical examination which includes a psychosocial evaluation . RESULTS: A decrease in systolic blood pressure (SBP) from session 1 to session 2 was found in subjects with low pain severity scores, but not in those with high pain severity scores. High scores for pain catastrophizing/ magnification and pain-related emotional distress were independently associated respectively with a SBP increase at an early-point in time and a SBP decrease at a mid-point in time after standing up from lying down. Stronger heart rate reactivity responses to orthostatic challenge indicated greater protection against the presence of these chronic pain symptoms. CONCLUSIONS: This biobehavioral protocol enables measurement of chronic pain suffering and protection in three dimensions: physical, emotional, and cognitive.

Resilience to orthostasis and haemorrhage: A pilot study of common genetic and conditioning mechanisms.

A major challenge presently is not only to identify the genetic polymorphisms increasing risk to diseases, but to also find out factors and mechanisms, which can counteract a risk genotype by developing a resilient phenotype. The objective of this study was to examine acquired and innate vagal mechanisms that protect against physical challenges and haemorrhages in 19 athletes and 61 non-athletes. These include examining change in heart rate variability (HF-HRV; an indicator of vagus activity) in response to orthostatic challenge, platelet count (PLT), mean platelet volume (MPV), and single-nucleotide polymorphisms in genes that encode several coagulation factors, PAI-1, and MTHFR. Individual differences in PLT and MPV were significant predictors, with opposite effects, of the profiles of the HF-HRV changes in response to orthostasis. Regular physical training of athletes indirectly (through MPV) modifies the genetic predisposing effects of some haemostatic factors (PAI-1 and MTHFR) on vagal tone and reactivity. Individual differences in vagal tone were also associated with relationships between Factor 12 C46T and Factor 11 C22771T genes polymorphisms. This study showed that genetic predispositions for coagulation are modifiable. Its potential significance is promoting advanced protection against haemorrhages in a variety of traumas and injuries, especially in individuals with coagulation deficits.

Heroin abusers' performance on the Tower of London Test relates to the baseline EEG alpha2 mean frequency shifts.

Planning function deficit is the most consistent finding in neuropsychological studies of heroin addicts. The performance on the Tower of London Test (TLT) correlated with the duration of daily heroin abuse (DDHA) in our previous study. Alpha2 mean frequency in anterior/central derivations was also predicted by DDHA in the same patient population. This retrospective study was undertaken in order to understand better the relationships between observed neurological deviations in heroin abusers. Thirty-three heroin addicts and 12 healthy males were evaluated with 14 neuropsychological tests and resting eyes-closed electroencephalography (EEG). Multivariate tests showed that performance on the difficult (five-move) problems of TLT was strongly predicted by the EEG alpha2 mean frequency shifts, and these relationships were generally mediated by chronic heroin length. However, post-hoc analyses at separate leads demonstrated that the relationships between cognitive variables and alpha2 mean frequencies in the left hemisphere were independent of chronic heroin effects, whereas elevation of alpha2 frequency in the right hemisphere was strongly predicted by chronic heroin intake length. The patients with extremely high alpha2 mean frequency at the left central region were especially prone to failure in TLT due to the inability of the hypothesized alpha2-generating network, which normally projects to the central and temporal derivations bilaterally and to the right posterior temporal derivation to function appropriately. Hence, it was concluded that planning dysfunction in heroin abusers is related to alpha2 mean frequency shifts predominantly at the central regions.

Moods in everyday situations: effects of menstrual cycle, work, and personality.

OBJECTIVE: This study examined women's moods on work and off days during different phases of the menstrual cycle. METHOD: Self-reports of the moods angry, happy, sad, stressed, tired, and anxious were obtained on two work and two off days during the luteal and follicular phases of the menstrual cycle in 203 nurses. Individual differences in anger expression, anxiety, and hostility were assessed. RESULTS: Ratings of anxious, stressed, and tired were higher and happy and sad were lower on the workday than the off day. Menstrual cycle phase was associated with mood differences depending on the day (work, off work) and individual differences in personality traits. CONCLUSIONS: The experience of moods in everyday life is affected by overall levels of stress and phase of the menstrual cycle. The findings suggest the need to refine sociopsychobiological and clinical models of mood regulation and of risk for disease.

Situations and moods associated with smoking in everyday life.

On 4 days, in everyday situations, 21 female and 26 male smokers used an electronic diary to record situations and moods at times of smoking and at control nonsmoking occasions. Self-reports of particular locations, activities, posture, consumption, social context, moods, and internal states were specifically associated with smoking. Real-time assessments in everyday situations provide useful information about the interplay of environmental factors and internal states in smoking. The findings suggest that conditioning and learning processes play a role in smoking and should be considered in smoking cessation programs.