Three weeks of mental training changes physiological outcomes during a time trial to exhaustion.

Mental training (MT) can increase endurance performance. The purpose of this study was to examine the minimum dose of mental training needed to increase performance and elucidate the physiological mechanisms underlying this improvement. In a randomized between groups pre-test-post-test design, 33 participants visited the lab on 6 separate days. A VO2peak with ventilatory threshold (VT) was performed on day 1. The subsequent visits consisted of time trials to exhaustion (TTE) performed at 10% above VT. Between visit 3 and 6, the MT group (n = 16) watched a video for 10-15 min each day for 3 weeks, while the control group (CON; n = 17) did no mental training. Heart rate (HR), rate of perceived exertion (RPE), VAS scores for pain and fatigue, electromyography, and metabolic and neuromuscular data were collected and recorded during the time trials. The GRIT-S and CD-RISC 10 surveys were completed before study days 3 and 6. TTE increased significantly for MT beginning after 2 weeks (10.0 ± 13.1%) with no further change after 3 weeks (10.4 ± 13.2). TTE also significantly decreased during the last TTE for CON (-10.3 ± 12.7). VO2, ventilation, and frequency of breathing were significantly reduced in the latter stages of the TTE for MT. EMG was also significantly decreased for MT as compared for CON throughout the trial. Three weeks of mental training improves performance by reducing EMG, decreasing activation of the muscle and reducing metabolic factors during the latter stages of exercise.

Fatigue sensation and gene expression in trained cyclists following a 40 km time trial in the heat.

PURPOSE: We examined the effect of race-effort cycling exercise with and without heat stress on post-exercise perceptions of fatigue and pain, as well as mRNA expression in genes related to exercise responses. METHODS: Trained cyclists (n = 20) completed 40 km time trials during temperate (TC, 21 °C) and hot (HC, 35 °C) conditions. Blood lactates were measured 1 and 5 min post-exercise. Venous blood samples and ratings of fatigue and pain perceptions were obtained at baseline and at 0.5, 8, 24, and 48 h post-exercise. Leukocyte mRNA expression was performed for metabolite detecting, adrenergic, monoamine, and immune receptors using qPCR. RESULTS: Significantly lower mean power (157 ± 32.3 vs 187 ± 40 W) and lactates (6.4 ± 1.7 vs 8.8 ± 3.2 and 4.2 ± 1.5 vs 6.6 ± 2.7 mmol L(-1) at 1- and 5-min post-exercise) were observed for HC versus TC, respectively (p < 0.05). Increases (p < 0.05) in physical fatigue and pain perception during TTs did not differ between TC and HC (p > 0.30). Both trials resulted in significant post-exercise decreases in metabolite detecting receptors ASIC3, P2X4, TRPV1, and TRPV4; increases in adrenergic receptors α2a, α2c, and ß1; decreases in adrenergic ß2, the immune receptor TLR4, and dopamine (DRD4); and increases in serotonin (HTR1D) and IL-10 (p < 0.05). Post-exercise IL-6 differed between TC and HC, with significantly greater increases observed following HC (p < 0.05). CONCLUSIONS: Both TT performances appeared to be regulated around a specific sensory perception of fatigue and pain. Heat stress may have compensated for lower lactate during HC, thereby matching changes in metabolite detecting and other mRNAs across conditions.

Effect of Pregabalin on Cardiovascular Responses to Exercise and Postexercise Pain and Fatigue in Fibromyalgia: A Randomized, Double-Blind, Crossover Pilot Study.

Pregabalin, an approved treatment for fibromyalgia (FM), has been shown to decrease sympathetic nervous system (SNS) activity and inhibit sympathetically maintained pain, but its effects on exercise responses have not been reported. Methods. Using a randomized double-blind crossover design, we assessed the effect of 5 weeks of pregabalin (versus placebo) on acute cardiovascular and subjective responses to moderate exercise in 19 FM patients. Blood pressure (BP), heart rate (HR), and ratings of perceived exertion (RPE) during exercise and ratings of pain, physical fatigue, and mental fatigue before, during, and for 48 hours after exercise were compared in patients on pregabalin versus placebo and also versus 18 healthy controls. Results. On placebo, exercise RPE and BP were significantly higher in FM patients than controls (p < 0.04). Pregabalin responders (n = 12, defined by patient satisfaction and symptom changes) had significantly lower exercise BP, HR, and RPE on pregabalin versus placebo (p < 0.03) and no longer differed from controls (p > 0.26). Cardiovascular responses of nonresponders (n = 7) were not altered by pregabalin. In responders, pregabalin improved ratings of fatigue and pain (p < 0.04), but negative effects on pain and fatigue were seen in nonresponders. Conclusions. These preliminary findings suggest that pregabalin may normalize cardiovascular and subjective responses to exercise in many FM patients.

Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects.

NEW FINDINGS: What is the central question of this study? Can physiological concentrations of metabolite combinations evoke sensations of fatigue and pain when injected into skeletal muscle? If so, what sensations are evoked? What is the main finding and its importance? Low concentrations of protons, lactate and ATP evoked sensations related to fatigue. Higher concentrations of these metabolites evoked pain. Single metabolites evoked no sensations. This suggests that the combination of an ASIC receptor and a purinergic P2X receptor is required for signalling fatigue and pain. The results also suggest that two types of sensory neurons encode metabolites; one detects low concentrations of metabolites and signals sensations of fatigue, whereas the other detects higher levels of metabolites and signals ache and hot. The perception of fatigue is common in many disease states; however, the mechanisms of sensory muscle fatigue are not understood. In mice, rats and cats, muscle afferents signal metabolite production in skeletal muscle using a complex of ASIC, P2X and TRPV1 receptors. Endogenous muscle agonists for these receptors are combinations of protons, lactate and ATP. Here we applied physiological concentrations of these agonists to muscle interstitium in human subjects to determine whether this combination could activate sensations and, if so, to determine how the subjects described these sensations. Ten volunteers received infusions (0.2 ml over 30 s) containing protons, lactate and ATP under the fascia of a thumb muscle, abductor pollicis brevis. Infusion of individual metabolites at maximal amounts evoked no fatigue or pain. Metabolite combinations found in resting muscles (pH 7.4 + 300 nm ATP + 1 mm lactate) also evoked no sensation. The infusion of a metabolite combination found in muscle during moderate endurance exercise (pH 7.3 + 400 nm ATP + 5 mm lactate) produced significant fatigue sensations. Infusion of a metabolite combination associated with vigorous exercise (pH 7.2 + 500 nm ATP + 10 mm lactate) produced stronger sensations of fatigue and some ache. Higher levels of metabolites (as found with ischaemic exercise) caused more ache but no additional fatigue sensation. Thus, in a dose-dependent manner, intramuscular infusion of combinations of protons, lactate and ATP leads to fatigue sensation and eventually pain, probably through activation of ASIC, P2X and TRPV1 receptors. This is the first demonstration in humans that metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain.

Dysregulation of leukocyte gene expression in women with medication-refractory depression versus healthy non-depressed controls.

BACKGROUND: Depressive Disorders (DD) are a great financial and social burden. Females display 70% higher rate of depression than males and more than 30% of these patients do not respond to conventional medications. Thus medication-refractory female patients are a large, under-served, group where new biological targets for intervention are greatly needed. METHODS: We used real-time quantitative polymerase chain reaction (qPCR) to evaluate mRNA gene expression from peripheral blood leukocytes for 27 genes, including immune, HPA-axis, ion channels, and growth and transcription factors. Our sample included 23 females with medication refractory DD: 13 with major depressive disorder (MDD), 10 with bipolar disorder (BPD). Our comparison group was 19 healthy, non-depressed female controls. We examined differences in mRNA expression in DD vs. controls, in MDD vs. BPD, and in patients with greater vs. lesser depression severity. RESULTS: DD patients showed increased expression for IL-10, IL-6, OXTR, P2RX7, P2RY1, and TRPV1. BPD patients showed increased APP, CREB1, NFKB1, NR3C1, and SPARC and decreased TNF expression. Depression severity was related to increased IL-10, P2RY1, P2RX1, and TRPV4 expression. CONCLUSIONS: These results support prior findings of dysregulation in immune genes, and provide preliminary evidence of dysregulation in purinergic and other ion channels in females with medication-refractory depression, and in transcription and growth factors in those with BPD. If replicated in future research examining protein levels as well as mRNA, these pathways could potentially be used to explore biological mechanisms of depression and to develop new drug targets.

Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome.

BACKGROUND: Androgen deprivation therapy (ADT) often worsens fatigue in patients with prostate cancer, producing symptoms similar to chronic fatigue syndrome (CFS). Comparing expression (mRNA) of many fatigue-related genes in patients with ADT-treated prostate cancer versus with CFS versus healthy controls, and correlating mRNA with fatigue severity may clarify the differing pathways underlying fatigue in these conditions. METHODS: Quantitative real-time PCR was performed on leukocytes from 30 fatigued, ADT-treated prostate cancer patients (PCF), 39 patients with CFS and 22 controls aged 40-79, together with ratings of fatigue and pain severity. 46 genes from these pathways were included: (1) adrenergic/monoamine/neuropeptides, (2) immune, (3) metabolite-detecting, (4) mitochondrial/energy, (5) transcription factors. RESULTS: PCF patients showed higher expression than controls or CFS of 2 immune transcription genes (NR3C1 and TLR4), chemokine CXCR4, and mitochondrial gene SOD2. They showed lower expression of 2 vasodilation-related genes (ADRB2 and VIPR2), 2 cytokines (TNF and LTA), and 2 metabolite-detecting receptors (ASIC3 and P2RX7). CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=-0.50, p<0.005 and r=-0.34, p<0.05). Purinergic P2RY1 was correlated only with PCF fatigue and pain severity (r=+0.43 and +0.59, p=0.025 and p=0.001). CONCLUSIONS: PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue.

Effect of passive whole body heating on central conduction and cortical excitability in multiple sclerosis patients and healthy controls.

Heat stress is associated with increased fatigue perception and decrements in function for individuals with multiple sclerosis (MS). Similarly, healthy individuals experience decrements in exercise performance during hyperthermia. Alterations in central nervous system (CNS) function during hyperthermia include reduced voluntary activation of muscle and increased effort perception. The purpose of this investigation was to test the hypothesis that passive heat exposure in MS patients will produce increased subjective fatigue and impairments in physiological measures of central conduction and cortical excitability compared with healthy individuals. Eleven healthy individuals and 11 MS patients completed a series of transcranial magnetic stimulation studies to examine central conduction and cortical excitability under thermoneutral and heat-stressed (HS) conditions at rest and after a fatiguing thumb abduction task. Passive heat stress resulted in significantly greater fatigue perception and impairments in force production in MS patients. Central motor conduction time was significantly shorter during HS in controls; however, in MS patients normal increases in conduction velocity with increased temperature were not observed centrally. MS patients also exhibited decreased cortical excitability during HS, evidenced by significant increases in resting motor threshold, decreased MEP amplitude, and decreased recruitment curve slope. Both groups exhibited postexercise depression of MEP amplitude, but the magnitude of these decrements was amplified in MS patients during HS. Taken together, these results suggest that CNS pathology in MS patients played a substantial role in reducing cortical excitability during HS.

Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls.

OBJECTIVE: Chronic fatigue syndrome (CFS) and multiple sclerosis (MS) are characterized by debilitating fatigue, yet evaluation of this symptom is subjective. We examined metabolite-detecting, adrenergic, and immune gene expression (messenger ribonucleic acid [mRNA]) in patients with CFS (n = 22) versus patients with MS (n = 20) versus healthy controls (n = 23) and determined their relationship to fatigue and pain before and after exercise. METHODS: Blood samples and fatigue and pain ratings were obtained at baseline and 0.5, 8, 24, and 48 hours after sustained moderate exercise. Leukocyte mRNA of four metabolite-detecting receptors (acid-sensing ion channel 3, purinergic type 2X4 and 2X5 receptors, and transient receptor potential vanilloid type 1) and four adrenergic (α-2a, ß-1, and ß-2 receptors and catechol-O-methyltransferase) and five immune markers (CD14, toll-like receptor 4 [TLR4], interleukin [IL] 6, IL-10, and lymphotoxin α) was examined using quantitative polymerase chain reaction. RESULTS: Patients with CFS had greater postexercise increases in fatigue and pain (10-29 points above baseline, p < .001) and greater mRNA increases in purinergic type 2X4 receptor, transient receptor potential vanilloid type 1, CD14, and all adrenergic receptors than controls (mean ± standard error = 1.3 ± 0.14- to 3.4 ± 0.90-fold increase above baseline, p = .04-.005). Patients with CFS with comorbid fibromyalgia (n = 18) also showed greater increases in acid-sensing ion channel 3 and purinergic type 2X5 receptors (p < .05). Patients with MS had greater postexercise increases than controls in ß-1 and ß-2 adrenergic receptor expressions (1.4 ± 0.27- and 1.3 ± 0.06-fold increases, respectively, p = .02 and p < .001) and greater decreases in TLR4 (p = .02). In MS, IL-10 and TLR4 decreases correlated with higher fatigue scores. CONCLUSIONS: Postexercise mRNA increases in metabolite-detecting receptors were unique to patients with CFS, whereas both patients with MS and patients with CFS showed abnormal increases in adrenergic receptors. Among patients with MS, greater fatigue was correlated with blunted immune marker expression.