A Methodological Framework to Capture Neuromuscular Fatigue Mechanisms Under Stress

Neuromuscular fatigue is exacerbated under stress and is characterized by shorter endurance time, greater perceived effort, lower force steadiness, and higher electromyographic activity. However, the underlying mechanisms of fatigue under stress are not well-understood. This review investigated existing methods of identifying central mechanisms of neuromuscular fatigue and the potential mechanisms of the influence of stress on neuromuscular fatigue. We found that the influence of stress on the activity of the prefrontal cortex, which are also involved in exercise regulation, may contribute to exacerbated fatigue under stress. We also found that the traditional methods involve the synchronized use of transcranial magnetic stimulation, peripheral nerve stimulation, and electromyography to identify the contribution of supraspinal fatigue, through measures such as voluntary activation, motor evoked potential, and silent period. However, these popular techniques are unable to provide information about neural alterations upstream of the descending drive that may contribute to supraspinal fatigue development. To address this gap, we propose that functional brain imaging techniques, which provide insights on activation and information flow between brain regions, need to be combined with the traditional measures of measuring central fatigue to fully understand the mechanisms behind the influence of stress on fatigue.

Metabolomic impacts of branched-chain amino acid supplementation during endurance exercise: a crossover study

BackgroundSerotonin syntheses in the brain requires a steady supply of tryptophan. Branched chain amino acids (BCAA) and tryptophan are transported across the blood-brain barrier by the amino acid transporter LAT1. BCAA supplementation is predicted to decrease serotonin biosynthesis through LAT1 competition and reduce central fatigue during exercise. Despite a strong theoretical basis for BCAA to attenuate serotonin production and fatigue during exercise, a number of human clinical trials have failed to demonstrate these benefits. To shed light on this discrepancy, we measured the impact of BCAA supplementation on serotonin and associated metabolites during exercise.MethodsA cohort of endurance runners (n=10) participated in a randomized, placebo-controlled, crossover trial to determine impact of BCAA supplementation during a 60-minute run at 65% of VO2 max. Metabolomic analysis targeted for serotonin and untargeted analysis for biomarkers of BCAA supplementation using LCMS were performed on serum samples collected immediately before and after exercise.ResultsSerum BCAA levels were greater in the supplement group compared to placebo (p<0.05). Serum serotonin was lower immediately after BCAA supplementation and before exercise (p<0.05) but not after exercise. L-ornithine increased during exercise with BCAA treatment compared to placebo. Ratings of perceived exertion were no different in BCAA and placebo groups.ConclusionsBCAA supplementation led to a rapid decrease in serum serotonin concentration relative to placebo, which may be indicative of a central nervous system (CNS) mediated process. After exercise with BCAA supplementation, endurance athletes did not show lower serum serotonin concentration, but did present an almost three-fold increase in L-ornithine which has metabolic connections to cortisol and central fatigue.Trial Registration: ClinicalTrials.gov NCT04969536, retrospectively registered 20 July 2021, https://clinicaltrials.gov/ct2/show/NCT04969536

Comparative study between transcranial direct current and repetitive transcranial electromagnetic stimulation in the rehabilitation of primary fibromyalgia

Background Fibromyalgia syndrome (FMS) is a complex disorder where a widespread musculoskeletal pain (without a clear lesion basis) is associated with a great variety of symptoms including affective disturbances, central fatigue, cognitive dysfunction and even a particular skin reactivity to several chemical substances. Despite intense research effort, especially in the last years, the pathophysiology of the disease remains to be explained. The treatment recommendations were classified as pharmacological therapies, non-pharmacological treatments, and complementary non-pharmacological therapies. Also, particular interest has been raised by techniques able to perform effective modulation of brain areas through magnetic or electric currents applied to the scalp like transcranial magnetic and electrical stimulation such as direct current (TMS and tDCS). Objective: To compare the efficacy of Repetitive transcranial magnetic stimulation (r-TMS) and transcranial direct current stimulation (t-DCS) as non- invasive brain stimulation techniques in the rehabilitation of patients with primary (1ry) fibromyalgia (FM). Patients and Methods The present study included 30 patients with 1ry FM, equally divided into 2 groups. Group I included 15 patients who received 8 sessions of rTMS and Group II included 15 patients who received 8 sessions of anodal tDCS. Differences in visual analogue scale (VAS) of pain, tender point scale, Fibromyalgia Impact Questionnaire (FIQ) and Hospital Anxiety and Depression Scale (HADS) were assessed before and after completion of assigned treatment sessions. Results Pain VAS, tender point scale, FIQ and HADS showed significant decrease between baseline and follow-up assessments for both groups. Moreover, a significant change in all assessment scales was observed post treatment when compared between both groups with more significant improvement in the group received rTMS. Conclusion Both rTMS and tDCS techniques showed marked improvement in symptoms of pain, functional status and quality of life in patients with 1ry fibromyalgia. Both techniques can be considered as promising alternatives therapeutic options in the treatment of FM in order to reduce side effects of long-term use of drugs.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Neurological Entity?

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disorder of unknown physiopathology with multisystemic repercussions, framed in ICD-11 under the heading of neurology (8E49). There is no specific test to support its clinical diagnosis. Our objective is to review the evidence in neuroimaging and dysautonomia evaluation in order to support the neurological involvement and to find biomarkers serving to identify and/or monitor the pathology. The symptoms typically appear acutely, although they can develop progressively over years; an essential trait for diagnosis is “central” fatigue together with physical and/or mental exhaustion after a small effort. Neuroimaging reveals various morphological, connectivity, metabolic, and functional alterations of low specificity, which can serve to complement the neurological study of the patient. The COMPASS-31 questionnaire is a useful tool to triage patients under suspect of dysautonomia, at which point they may be redirected for deeper evaluation. Recently, alterations in heart rate variability, the Valsalva maneuver, and the tilt table test, together with the presence of serum autoantibodies against adrenergic, cholinergic, and serotonin receptors were shown in a subgroup of patients. This approach provides a way to identify patient phenotypes. Broader studies are needed to establish the level of sensitivity and specificity necessary for their validation. Neuroimaging contributes scarcely to the diagnosis, and this depends on the identification of specific changes. On the other hand, dysautonomia studies, carried out in specialized units, are highly promising in order to support the diagnosis and to identify potential biomarkers. ME/CFS orients towards a functional pathology that mainly involves the autonomic nervous system, although not exclusively.

Korean Red Ginseng Ameliorates Fatigue via Modulation of 5-HT and Corticosterone in a Sleep-Deprived Mouse Model

Central fatigue, which is neuromuscular dysfunction associated with neurochemical alterations, is an important clinical issue related to pathologic fatigue. This study aimed to investigate the anti-central fatigue effect of Korean red ginseng (KRG) and its underlying mechanism. Male BALB/c mice (8 weeks old) were subjected to periodic sleep deprivation (SD) for 6 cycles (forced wakefulness for 2 days + 1 normal day per cycle). Simultaneously, the mice were administered KRG (0, 100, 200, or 400 mg/kg) or ascorbic acid (100 mg/kg). After all cycles, the rotarod and grip strength tests were performed, and then the changes regarding stress- and neurotransmitter-related parameters in serum and brain tissue were evaluated. Six cycles of SD notably deteriorated exercise performance in both the rotarod and grip strength tests, while KRG administration significantly ameliorated these alterations. KRG also significantly attenuated the SD-induced depletion of serum corticosterone. The levels of main neurotransmitters related to the sleep/wake cycle were markedly altered (serotonin was overproduced while dopamine levels were decreased) by SD, and KRG significantly attenuated these alterations through relevant molecules including brain-derived neurotropic factor and serotonin transporter. This study demonstrated the anti-fatigue effects of KRG in an SD mouse model, indicating the clinical relevance of KRG.