Exercise does not cause post-exertional malaise in Veterans with Gulf War Illness: A randomized, controlled, dose-response, crossover study.

Chronic multisymptom illnesses (CMI) such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Long-COVID, and Gulf War Illness (GWI) are associated with an elevated risk of post-exertional malaise (PEM), an acute exacerbation of symptoms and other related outcomes following exercise. These individuals may benefit from personalized exercise prescriptions which prioritize risk minimization, necessitating a better understanding of dose-response effects of exercise intensity on PEM. METHODS: Veterans with GWI (n = 40) completed a randomized controlled crossover experiment comparing 20 min of seated rest to light-, moderate-, and vigorous-intensity cycling conditions over four separate study visits. Symptoms, pain sensitivity, cognitive performance, inflammatory markers (C-reactive protein and plasma cytokines) were measured before and within 1 h after exercise and seated rest. Physical activity behavior was measured ≥ 7 days following each study visit via actigraphy. Linear mixed effects regression models tested the central hypothesis that higher intensity exercise would elicit greater exacerbation of negative outcomes, as indicated by a significant condition-by-time interaction for symptom, pain sensitivity, cognitive performance, and inflammatory marker models and a significant main effect of condition for physical activity models. RESULTS: Significant condition-by-time interactions were not observed for primary or secondary measures of symptoms, pain sensitivity, cognitive performance, and a majority of inflammatory markers. Similarly, a significant effect of condition was not observed for primary or secondary measures of physical activity. CONCLUSIONS: Undesirable effects such as symptom exacerbation were observed for some participants, but the group-level risk of PEM following light-, moderate-, or vigorous-intensity exercise was no greater than seated rest. These findings challenge several prior views about PEM and lend support to a broader body of literature showing that the benefits of exercise outweigh the risks.

Post-COVID-19 Syndrome Clinical Pathway for the US Veterans Health Administration.

The Department of Veterans Health Affairs (VHA) has launched 22 multispecialty post-COVID-19 clinics across the US for the growing number of veterans experiencing long-term sequelae after acute COVID-19 infection. While evidence-based treatments for this syndrome are under investigation, there is a critical need to establish and disseminate clinical pathways (CPWs) based on knowledge and experience gained in those clinics. This VHA CPW is intended to guide primary care clinicians who care for patients experiencing dyspnea and/or cough during post-COVID-19 syndrome (PCS), which includes symptoms and abnormalities persisting or present beyond 12 weeks of the onset of acute COVID-19. This effort will help guide and standardize the care of veterans across the VHA, improve health outcomes, and effectively utilize health care resources. This article summarizes our stepwise diagnostic approach for patients presenting with PCS dyspnea and/or cough in primary care; it also highlights teleconsultation and telerehabilitation as opportunities to reach those in rural areas or with transportation barriers and improve reach for specialized services.

Deployed Veterans exhibit distinct respiratory patterns and greater dyspnea during maximal cardiopulmonary exercise: A case-control study.

BACKGROUND: Exertional dyspnea and exercise intolerance are frequently endorsed in Veterans of post 9/11 conflicts in Southwest Asia (SWA). Studying the dynamic behavior of ventilation during exercise may provide mechanistic insight into these symptoms. Using maximal cardiopulmonary exercise testing (CPET) to experimentally induce exertional symptoms, we aimed to identify potential physiological differences between deployed Veterans and non-deployed controls. MATERIALS AND METHODS: Deployed (n = 31) and non-deployed (n = 17) participants performed a maximal effort CPET via the Bruce treadmill protocol. Indirect calorimetry and perceptual rating scales were used to measure rate of oxygen consumption ([Formula: see text]), rate of carbon dioxide production ([Formula: see text]), respiratory frequency (f R), tidal volume (VT), minute ventilation ([Formula: see text]), heart rate (HR), perceived exertion (RPE; 6-20 scale), and dyspnea (Borg Breathlessness Scale; 0-10 scale). A repeated measures analysis of variance (RM-ANOVA) model (2 groups: deployed vs non-deployed X 6 timepoints: 0%, 20%, 40%, 60%, 80%, and 100% [Formula: see text]) was conducted for participants meeting valid effort criteria (deployed = 25; non-deployed = 11). RESULTS: Significant group (η2partial = 0.26) and interaction (η2partial = 0.10) effects were observed such that deployed Veterans exhibited reduced f R and a greater change over time relative to non-deployed controls. There was also a significant group effect for dyspnea ratings (η2partial = 0.18) showing higher values in deployed participants. Exploratory correlational analyses revealed significant associations between dyspnea ratings and fR at 80% (R2 = 0.34) and 100% (R2 = 0.17) of [Formula: see text], but only in deployed Veterans. CONCLUSION: Relative to non-deployed controls, Veterans deployed to SWA exhibited reduced fR and greater dyspnea during maximal exercise. Further, associations between these parameters occurred only in deployed Veterans. These findings support an association between SWA deployment and affected respiratory health, and also highlight the utility of CPET in the clinical evaluation of deployment-related dyspnea in Veterans.

Exercise-induced changes in gene expression do not mediate post exertional malaise in Gulf War illness.

Background: Post-exertional malaise (PEM) is considered a characteristic feature of chronic multi-symptom illnesses (CMI) like Gulf War illness (GWI); however, its pathophysiology remains understudied. Previous investigations in other CMI populations (i.e., Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) have reported associations between PEM and expression of genes coding for adrenergic, metabolic, and immune function. Objectives: To investigate whether PEM is meditated by gene expression in Veterans with GWI. Methods: Veterans with GWI (n = 37) and healthy control Gulf War Veterans (n = 25) provided blood samples before and after 30-min of cycling at 70% of age-predicted heart rate reserve. Relative quantification of gene expression, symptom measurements, and select cardiopulmonary parameters were compared between groups at pre-, 30 minpost-, and 24 hpost-exercise using a doubly multivariate repeated measures analysis of variance (RM-MANOVA). Mediation analyses were used to test indirect effects of changes in gene expression on symptom responses (i.e., PEM) to the standardized exercise challenge. Results: Veterans with GWI experienced large symptom exacerbations following exercise compared to controls (Cohen's d: 1.65; p < 0.05). Expression of ß -actin (ACTB), catechol-O-methyltransferase (COMT), and toll-like receptor 4 (TLR4) decreased in Veterans with GWI at 30 min (p < 0.05) and 24 h post-exercise (p < 0.05). Changes in gene expression did not mediate post-exercise symptom exacerbation in GWI (Indirect Effect Slope Coefficient: 0.06 - 0.02; 95% CI: 0.19, 0.12). Conclusion: An acute bout of moderate intensity cycling reduced the expression of select structural, adrenergic, and immune genes in Veterans with GWI, but the pathophysiological relevance to PEM is unclear.

The Interplay Between Expected Psychological Responses to Exercise and Physical Activity in Analogue Generalized Anxiety Disorder: a Cross-sectional Study.

BACKGROUND: Expectations for psychological responses to exercise are not well characterized, particularly in people at risk for anxiety-related illnesses. Given the substantial evidence for salutary effects of exercise on anxiety symptoms and emerging recognition for expectations as a critical mechanism of placebo/nocebo effects, this study explored the interplay between expectations and physical activity in young adults with and without analogue generalized anxiety disorder. METHODS: Participants (N=470, 23.2±4.8 years, 63% female) completed a physical activity and mood survey, including a 7-day physical activity recall questionnaire, and a 20-item questionnaire designed to measure positive and negative expectations for psychological and perceptual responses to exercise, particularly expectations for symptoms in the generalized anxiety disorder symptom profile. Analogue generalized anxiety disorder status was determined using the Generalized Anxiety Disorder subscale of the Psychiatric Diagnostic Screening Questionnaire. RESULTS: For select outcomes, expected exercise-induced changes significantly differed according to analogue generalized anxiety disorder (whole-body pain, sleep quality, psychological well-being, stress, relaxation) and active versus inactive (anxious mood, depressed mood, concentration, physical function, psychological well-being, relaxation) status. However, these findings did not survive corrections for multiple comparisons and the magnitude of these differences was small, approximating 0.25 standard deviations. Expectations for anxious (Spearman's ρ=-0.14, p≤0.002) and depressed mood (ρ=-0.15, p≤0.002), and psychological well-being (ρ=0.15, p≤0.001) were significantly associated with higher physical activity levels. Exercise expectations for anxious mood explained a significant, but small (+1.5%, p≤0.03), amount of variance in physical activity. CONCLUSIONS: Expectations for exercise-induced improvements did not significantly differ between young adults based on analogue generalized anxiety disorder or physical activity status.

Pain, but not Physical Activity, is Associated with Gray Matter Volume Differences in Gulf War Veterans with Chronic Pain.

Chronic musculoskeletal pain (CMP) is a significant burden for Persian Gulf War Veterans (GWV), yet the causes are poorly understood. Brain structure abnormalities are observed in GWV, however relationships with modifiable lifestyle factors such as physical activity (PA) are unknown. We evaluated gray matter volumes and associations with symptoms, PA, and sedentary time in GWV with and without CMP. Ninety-eight GWV (10 females) with CMP and 56 GWV (7 females) controls completed T1 weighted magnetic resonance imaging, pain and fatigue symptom questionnaires, and PA measurement via actigraphy. Regional gray matter volumes were analyzed using voxel-based morphometry and were compared across groups using analysis of covariance. Separate multiple linear regression models were used to test associations between PA intensities, sedentary time, symptoms, and gray matter volumes. Family-wise cluster error rates were used to control for multiple comparisons (α=0.05). GWV with CMP reported greater pain and fatigue symptoms, worse mood, and engaged in less moderate-to-vigorous PA and more sedentary time than healthy GWV (all p<0.05). GWV with CMP had smaller gray matter volumes in the bilateral insula and larger volumes in the frontal pole (p<0.05adjusted). Gray matter volumes in the left insula were associated with pain symptoms (rpartial=0.26, -0.29; p<0.05adjusted). No significant associations were observed for either PA or sedentary time (p>0.05adjusted). GWV with CMP had smaller gray matter volumes within a critical brain region of the descending pain processing network and larger volumes within brain regions associated with pain sensation and affective processing which may reflect pain chronification.Significance Statement:The pathophysiology of chronic pain in Gulf War Veterans is understudied and not well understood. In a large sample of Gulf War Veterans, we report Veterans with chronic musculoskeletal pain have smaller gray matter volumes in brain regions associated with pain regulation and larger volumes in regions associated with pain sensitivity compared to otherwise healthy Gulf War Veterans. Gray matter volumes in regions of pain regulation were significantly associated with pain symptoms and encompassed the observed group brain volume differences. These results are suggestive of deficient pain modulation that may contribute to pain chronification.

Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-study.

BACKGROUND: Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear. PURPOSE: To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness. METHODS: As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent ([Formula: see text], [Formula: see text]), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges' g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20-100% peak [Formula: see text]). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak [Formula: see text] (~1 ml/kg/min-1). RESULTS: Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20-100% peak [Formula: see text]) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for [Formula: see text], [Formula: see text] and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency, [Formula: see text], [Formula: see text], and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., [Formula: see text]) were generally reflective of those seen throughout exercise (i.e., 20-100%). CONCLUSION: Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS.

Pain-Related Post-Exertional Malaise in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia: A Systematic Review and Three-Level Meta-Analysis.

OBJECTIVE: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are two debilitating, moderately comorbid illnesses in which chronic musculoskeletal pain symptoms are prevalent. These individuals can experience post-exertional malaise (PEM), a phenomenon in which symptom severity is worsened for 24 hours or longer after physical stress, but the pain-related component of PEM is not well characterized. DESIGN: Systematic review and meta-analysis. METHODS: Case-control studies involving adults with ME/CFS or FM and measuring pain symptoms before and after exposure to a standardized aerobic exercise test were included. Hedges' d effect sizes were aggregated with random-effects models, and potential moderators were explored with meta-regression analysis. Results were adjusted for nesting effects with three-level modeling. RESULTS: Forty-five effects were extracted from 15 studies involving 306 patients and 292 healthy controls. After adjusting for nesting effects, we observed a small to moderate effect indicating higher post-exercise pain in patients than in controls (Hedges' d = 0.42; 95% confidence interval [CI]: 0.16-0.67). The mean effect was significantly moderated by pain measurement time point (b = -0.19, z = -2.57, P = 0.01), such that studies measuring pain 8-72 hours after exercise showed larger effects (d = 0.71, 95% CI = 0.28-1.14) than did those measuring pain 0-2 hours after exercise (d = 0.32, 95% CI = 0.10-0.53). CONCLUSIONS: People with ME/CFS and FM experience small to moderate increases in pain severity after exercise, which confirms pain as a component of PEM and emphasizes its debilitating impact in ME/CFS and FM. Future directions include determining mechanisms of pain-related PEM and developing exercise prescriptions that minimize symptom exacerbation in these illnesses.

A common language for Gulf War Illness (GWI) research studies: GWI common data elements.

AIMS: The Gulf War Illness programs (GWI) of the United States Department of Veteran Affairs and the Department of Defense Congressionally Directed Medical Research Program collaborated with experts to develop Common Data Elements (CDEs) to standardize and systematically collect, analyze, and share data across the (GWI) research community. MAIN METHODS: A collective working group of GWI advocates, Veterans, clinicians, and researchers convened to provide consensus on instruments, case report forms, and guidelines for GWI research. A similar initiative, supported by the National Institute of Neurologic Disorders and Stroke (NINDS) was completed for a comparative illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and provided the foundation for this undertaking. The GWI working group divided into two sub-groups (symptoms and systems assessment). Both groups reviewed the applicability of instruments and forms recommended by the NINDS ME/CFS CDE to GWI research within specific domains and selected assessments of deployment exposures. The GWI CDE recommendations were finalized in March 2018 after soliciting public comments. KEY FINDINGS: GWI CDE recommendations are organized in 12 domains that include instruments, case report forms, and guidelines. Recommendations were categorized as core (essential), supplemental-highly recommended (essential for specified conditions, study types, or designs), supplemental (commonly collected, but not required), and exploratory (reasonable to use, but require further validation). Recommendations will continually be updated as GWI research progresses. SIGNIFICANCE: The GWI CDEs reflect the consensus recommendations of GWI research community stakeholders and will allow studies to standardize data collection, enhance data quality, and facilitate data sharing.

Safety and efficacy of short-term structured resistance exercise in Gulf War Veterans with chronic unexplained muscle pain: A randomized controlled trial.

AIMS: Chronic widespread musculoskeletal pain (CMP) is a primary condition of Veterans suffering from Gulf War illness. This study evaluated the influence of resistance exercise training (RET) on symptoms, mood, perception of improvement, fitness, and total physical activity in Gulf War Veterans (GWV) with CMP. MAIN METHODS: Fifty-four GWV with CMP were randomly assigned to 16 weeks of RET (n = 28) or wait-list control (n = 26). Supervised exercise was performed twice weekly starting at a low intensity. Outcomes, assessed at baseline, 6, 11 and 17 weeks and 6- and 12-months post-intervention, were: pain, fatigue, mood, sleep quality, perception of improvement, and physical activity via self-report and accelerometry. Muscular strength was assessed at baseline, 8 and 16 weeks. Accelerometer data yielded estimates of time spent in sedentary, light, and moderate-to-vigorous physical activities. Analyses used separate linear mixed models with group and time point as fixed effects. All models, except for perceived improvement, included baseline values as a covariate. KEY FINDINGS: Participants assigned to RET completed 87% of training sessions and exhibited strength increases between 16 and 34% for eight lifts tested (Hedges' g range: 0.47-0.78). The treatment by time interaction for perceived improvement (F1,163 = 16.94, p < 0.001) was characterized by greater perceived improvement since baseline for RET at each time point, until the 12-month follow-up. Effects were not significant for other outcomes (p > 0.05). RET caused no adverse events. SIGNIFICANCE: After 16 weeks of RET, GWV with CMP reported improvements in their condition and exhibited increases in muscular strength, without symptom exacerbation or reductions in total physical activity.

Predicting post-exertional malaise in Gulf War Illness based on acute exercise responses.

AIMS: Post-exertional malaise (PEM) is poorly understood in Gulf War Illness (GWI). Exercise challenges have emerged as stimuli to study PEM; however, little attention has been paid to unique cardiorespiratory and perceptual responses during exercise. This study tested whether select exercise parameters explained variability in PEM responses. MAIN METHODS: Visual analog scale (0-100) versions of the Kansas questionnaire were used for daily symptom measurements one week before and one week after 30-min of cycling at 70% heart rate reserve in 43 Veterans with GWI and 31 Veteran controls (CON). Cardiopulmonary exercise testing (CPET) methods were used to measure oxygen (VO2), carbon dioxide (VCO2), ventilation (VE), heart rate, work rate, and leg muscle pain. Symptom changes and CPET parameters were compared between groups with independent samples t-tests. Linear regression (GLM) with VE/VCO2, cumulative work, leg muscle pain, and self-reported physical function treated as independent variables and peak symptom response as the dependent variable tested whether exercise responses predicted PEM. KEY FINDINGS: Compared to CON, Veterans with GWI had greater ventilatory equivalent for oxygen (VE/VO2), peak leg muscle pain, fatigue, and lower VCO2, VO2, power, and cumulative work during exercise (p < 0.05), and greater peak symptom responses (GWI = 38.90 ± 29.06, CON = 17.84 ± 28.26, g = 0.70, p < 0.01). The final GLM did not explain significant variance in PEM (Pooled R2 = 0.15, Adjusted R2 = 0.03, p = 0.34). SIGNIFICANCE: The PEM response was not related to the selected combination of cardiorespiratory and perceptual responses to exercise.

Nociceptive stress interferes with neural processing of cognitive stimuli in Gulf War Veterans with chronic musculoskeletal pain.

AIMS: Disrupted cognition and chronic musculoskeletal pain (CMP) are prevalent experiences among Gulf War Veterans (GWV). A negative association between CMP and cognition (i.e., chronic pain-related cognitive interference) has been observed in some chronic pain populations but has not been evaluated in GWV. Additional research suggests that disrupted cognition in GWV with CMP may be exacerbated by stressing the nociceptive system. Therefore, we compared cognitive performance and related neural activity between CMP and healthy control (CO) GWV in the absence and presence of experimental pain. MAIN METHODS: During functional magnetic resonance imaging (fMRI), Veterans (CMP = 29; CO = 27) completed cognitive testing via congruent and incongruent conditions of a modified Stroop task (Stroop-only). A random subset (CMP = 13; CO = 13) also completed cognitive testing with experimental pain (Pain+Stroop). Yuen's modified t-test and robust mixed-model analysis of variance (ANOVA) models were used for analyzing cognitive performance data. Independent t-tests and repeated-measures ANOVA models were employed for fMRI data with thresholding for multiple-comparisons (p < 0.005) and cluster size (> 320 mm3). KEY FINDINGS: Functional MRI analysis revealed significant between-group differences for the incongruent but not congruent-Stroop run. Neither correct responses nor reaction time differed between groups in either Stroop condition (all p ≥ 0.21). Significant group (CMP, CO) by run (Stroop-only, Pain+Stroop) interactions revealed greater neural responses in CMP Veterans during Pain+Stroop runs. No significant interactions were observed for correct responses or reaction time (p ≥ 0.31). SIGNIFICANCE: GWV with CMP require a greater amount of neural resources to sustain cognitive performance during nociceptive stress.

An analysis of 2-day cardiopulmonary exercise testing to assess unexplained fatigue.

Two consecutive maximal cardiopulmonary exercise tests (CPETs) performed 24 hr apart (2-day CPET protocol) are increasingly used to evaluate post-exertional malaise (PEM) and related disability among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This protocol may extend to other fatiguing illnesses with similar characteristics to ME/CFS; however, 2-day CPET protocol reliability and minimum change required to be considered clinically meaningful (i.e., exceeding the standard error of the measure) are not well characterized. To address this gap, we evaluated the 2-day CPET protocol in Gulf War Illness (GWI) by quantifying repeatability of seven CPET parameters, establishing their thresholds of clinically significant change, and determining whether changes differed between veterans with GWI and controls. Excluding those not attaining peak effort criteria (n = 15), we calculated intraclass correlation coefficients (ICCs), the smallest real difference (SRD%), and repeated measures analysis of variance (RM-ANOVA) at the ventilatory anaerobic threshold (VAT) and peak exercise in 15 veterans with GWI and eight controls. ICC values at peak ranged from moderate to excellent for veterans with GWI (mean [range]; 0.84 [0.65 - 0.92]) and were reduced at the VAT (0.68 [0.37 - 0.78]). Across CPET variables, the SRD% at peak exercise for veterans with GWI (18.8 [8.8 - 28.8]) was generally lower than at the VAT (28.1 [9.5 - 34.8]). RM-ANOVAs did not detect any significant group-by-time interactions (all p > .05). The methods and findings reported here provide a framework for evaluating 2-day CPET reliability, and reinforce the importance of carefully considering measurement error in the population of interest when interpreting findings.

Elevated Perceived Exertion in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Meta-analysis.

PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are two debilitating illnesses primarily characterized by chronic symptoms of fatigue and musculoskeletal pain, respectively. Some investigators have observed an elevated sense of effort in these patient groups; however, this effect has not been substantiated via quantitative review. As such, we conducted a meta-analysis of RPE responses to aerobic exercise in ME/CFS and FM compared with healthy adults. METHODS: Case-control studies involving adults with ME/CFS or FM that measured RPE and heart rate responses to acute aerobic exercise were included. Data sources included PubMed, Scopus/Embase, CINAHL, CENTRAL, and Google Scholar. Risk of bias was assessed by evaluating each study's description of participant characteristics, matching procedures, and administration of RPE scales. Hedges' d effect sizes for RPE were calculated and aggregated using random-effects models, and potential moderators were explored with meta-regression analysis. RESULTS: Forty-one effects were extracted from 37 studies involving 1016 patients and 686 healthy controls. We observed a large (Hedges' d = 0.85, 95% confidence interval = 0.62-1.08) effect indicating higher RPE in patients than controls. The mean effect size was significantly moderated (P < 0.001, R = 0.38) by whether RPE data were analyzed at a peak or submaximal intensity (b = 0.60, z = 4.6, P < 0.001) and the type of patient group that was studied (b = 0.25, z = 2.08, P = 0.04). CONCLUSIONS: People with ME/CFS and FM perceive aerobic exercise as more effortful than healthy adults, but the exact causes are unclear. The large magnitude of this effect merits further exploration of underlying mechanisms that could provide insight into the pathophysiology of ME/CFS and FM or the broader debate about the nature of central and/or peripheral signals that influence RPE.

Understanding placebo and nocebo effects in the context of sport: A psychological perspective.

Research over the past 15 years on the placebo effect has substantiated its contribution to the efficacy of established treatments for a range of clinical conditions and identified its underlying mechanisms. There is also evidence that placebo effects contribute to the performance benefits of many ergogenic aids, and that performance can worsen when dummy treatments are associated with expectations of a harmful outcome (i.e. nocebo effect). Unfortunately, the bulk of sport research involving placebos and nocebos continues to be hampered by outdated definitions and conceptualizations of placebo effects and their mechanisms. This has implications not only for research but also application, as nearly 50% of athletes report experiencing a beneficial placebo effect, and a similar proportion of coaches report providing placebos to their athletes. The objective of this paper is to attempt to stimulate research by presenting updated definitions of placebo and nocebo effects in the context of sport, describing their major mechanisms and, highlighting the importance of the psychosocial context on placebo effects in the sport setting.

Fitness, independent of physical activity is associated with cerebral blood flow in adults at risk for Alzheimer's disease.

Patterns of decreased resting cerebral blood flow (CBF) within the inferior temporal gyri, angular gyri, and posterior cingulate are a feature of aging and Alzheimer's disease (AD) and have shown to be predictive of cognitive decline among older adults. Fitness and physical activity are both associated with many indices of brain health and may positively influence CBF, however, the majority of research to date has examined these measures in isolation, leaving the potential independent associations unknown. The purpose of this study was to determine the unique contributions of fitness and physical activity when predicting CBF in cognitively healthy adults at risk for AD. One hundred participants (63% female) from the Wisconsin Registry for Alzheimer's Prevention underwent a maximal exercise test, physical activity monitoring, and a 3-D arterial spin labeling magnetic resonance imaging scan. For the entire sample, fitness was significantly associated with CBF while accounting for physical activity, age, gender, APOE ε4, family history of AD, education, and handedness (p = .026). Further, fitness explained significantly more variance than the combined effect of the covariates on CBF (R2 change = .059; p = .047). These results appear to be gender dependent, our data suggest fitness level, independent of physical activity, is associated with greater CBF in regions that are known to decline with age and AD for female (p = .011), but not male participants.

Advancing the understanding of placebo effects in psychological outcomes of exercise: Lessons learned and future directions.

Despite the apparent strength of scientific evidence suggesting that psychological benefits result from both acute and chronic exercise, concerns remain regarding the extent to which these benefits are explained by placebo effects. Addressing these concerns is methodologically and at times conceptually challenging. However, developments in the conceptualisation and study of placebo effects from the fields of psychology, neuroscience, pharmacology, and human performance offer guidance for advancing the understanding of placebo effects in psychological responses to exercise. In clinical trials, expectations can be measured and experimentally manipulated to better understand the influence of placebo effects on treatment responses. Further, compelling evidence has shown that the contribution of placebo effects and their underlying neurobiological mechanisms to treatment effects can be measured without administering a traditional placebo (e.g. inert substance) by leveraging psychological factors such as expectations and conditioning. Hence, the purpose of this focused review is to integrate lessons such as these with the current body of literature on placebo effects in psychological responses to exercise and provide recommendations for future research directions.

Reconceptualizing the measurement of expectations to better understand placebo and nocebo effects in psychological responses to exercise.

The understanding of placebo and nocebo effects in psychological responses to exercise may be improved by measuring expectations. Despite availability of several validated expectation measures, we argue for using scales that take both positive and negative expectations for exercise-induced changes into account. A cross-sectional survey was used to collect information on positive and negative expectations pertaining to how exercise would affect 14 different outcomes related to psychological health (n = 966). Outcomes for which a majority of the sample (>50%) reported positive expectations for exercise-induced changes included: psychological well-being (75.3%), depression (74.3%), relaxation (74.2%), sleep quality (73.3%), stress (72.2%), anxiety (69.8%), energy (67.1%), and attention (60.2%). Outcomes for which a majority of the sample (>50%) reported a negative expectation for exercise-induced changes were muscle pain (66.3%), fatigue (57.3%), and joint pain (50.7%). Across all 14 outcomes, the percentage of participants with negative expectations for exercise-induced changes ranged from 5.9 to 66.3%. Elucidating the potential presence of placebo and nocebo effects through measurement of expectations may improve the understanding of variability in the direction and magnitude of exercise-related effects on psychological health. Although there were only 3 outcomes for which the majority of participants reported negative expectations, we found that negative expectations were present to some degree for all 14 outcomes. Thus, for researchers who wish to characterize expectations in studies of psychological responses to exercise, we recommend using measures that give equal consideration to positive and negative expectations.

Post-exertional malaise in veterans with gulf war illness.

Post-exertional malaise (PEM) is a potentially debilitating aspect of Gulf War Illness (GWI) that has received limited research attention. The purpose of the present investigation was to determine symptom severity changes following exercise in Veterans with GWI compared to control Veterans without GWI (CO). Sixty-seven Veterans (n = 39 GWI; n = 28 CO) underwent a 30-minute submaximal exercise challenge at 70% of heart rate reserve. Symptom measurements (e.g. fatigue, pain) occurred pre-, immediately post-, and 24-hour post-exercise. Self-reported physical and mental health, and physiological and perceptual responses to exercise were compared between groups using descriptive statistics, independent samples t-tests and repeated measures Analysis of Variance (RM-ANOVA). Post-exertional malaise was modeled using Group by Time (2 × 3) doubly-multivariate, RM-MANOVAs for (1) mood, (2) pain and (3) GWI-related symptoms, respectively (α = 0.05). Data were analyzed for the full sample of Veterans with GWI (n = 39) compared to CO (n = 28) and a subsample of Veterans (n = 18) who endorsed "feeling unwell after physical exercise or exertion" ("PEM endorsers") during screening. Veterans with GWI reported significantly lower physical and mental health. Groups exercised at similar relative exercise intensities, but GWI perceived exercise as more painful and fatiguing. Group-by-Time interactions were not significant for the entire sample for the three PEM models, however limiting the GWI sample to "PEM endorsers" resulted in significant interactions for Pain- and GWI-related PEM models. These results indicate that not all GVs with GWI experience PEM 24 h after exercise, and that more research is needed to determine the extent that exercise worsens symptoms in GWI.

Veterans with Gulf War Illness exhibit distinct respiratory patterns during maximal cardiopulmonary exercise.

INTRODUCTION: The components of minute ventilation, respiratory frequency and tidal volume, appear differentially regulated and thereby afford unique insight into the ventilatory response to exercise. However, respiratory frequency and tidal volume are infrequently reported, and have not previously been considered among military veterans with Gulf War Illness. Our purpose was to evaluate respiratory frequency and tidal volume in response to a maximal cardiopulmonary exercise test in individuals with and without Gulf War Illness. MATERIALS AND METHODS: 20 cases with Gulf War Illness and 14 controls participated in this study and performed maximal cardiopulmonary exercise test on a cycle ergometer. Ventilatory variables (minute ventilation, respiratory frequency and tidal volume) were obtained and normalized to peak exercise capacity. Using mixed-design analysis of variance models, with group and time as factors, we analyzed exercise ventilatory patterns for the entire sample and for 11 subjects from each group matched for race, age, sex, and height. RESULTS: Despite similar minute ventilation (p = 0.57, η2p = 0.01), tidal volume was greater (p = 0.02, η2p = 0.16) and respiratory frequency was lower (p = 0.004, η2p = 0.24) in Veterans with Gulf War Illness than controls. The findings for respiratory frequency remained significant in the matched subgroup (p = 0.004, η2p = 0.35). CONCLUSION: In our sample, veterans with Gulf War Illness adopt a unique exercise ventilatory pattern characterized by reduced respiratory frequency, despite similar ventilation relative to controls. Although the mechanism(s) by which this pattern is achieved remains unresolved, our findings suggest that the components of ventilation should be considered when evaluating clinical conditions with unexplained exertional symptoms.