Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment.

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood-brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

Mental fatigue impairs physical activity, technical and decision-making performance during small-sided games.

The aim of this study was to investigate the effects of mental fatigue on physical activity, technical and decision-making performance during small-sided games. Nine sub-elite soccer players were enrolled in the study. The players performed two small-sided games on two occasions within a crossover experimental design. Before each game, they underwent a mental fatiguing task (Stroop task) and a control task (documentary watching) in a randomized, counterbalanced order. Players' physical activity, technical, and decision-making performance were obtained during small-sided games by GPS and video scouting. Results showed that distance in acceleration covered per min, negative passes, passing accuracy, and shot accuracy were likely impaired than control task after a mental fatiguing protocol. Decision-making performance of negative passes, passes accuracy, and dribbling accuracy resulted also likely decreased compared with control task. These findings demonstrated that mental fatigue impacted on technical, GPS-derived, and soccer-specific decision-making performance during SSG. In conclusion, avoiding cognitively demanding tasks before playing soccer-specific activities may be advisable to preserve players' physical activity, technical, and decision-making skills.

Application of LC-MS-Based Global Metabolomic Profiling Methods to Human Mental Fatigue.

Mental fatigue is characterized by a reduced capacity for work and a loss of capacity to respond to stimulation and is usually accompanied by a feeling of tiredness and drowsiness. Mental fatigue at work is a serious problem and can raise safety concerns especially in the transportation system. It is believed that mental fatigue is a direct or contributing cause of road and air related accidents and incidents. Psychological studies indicate that fatigue results in reduced work efficiency, alertness, and impaired mental performance. However, its underlying biochemical mechanisms are poorly understood. We hypothesized that the human body is an integrated system, and mental fatigue results in changes not only in psychology but also in biochemistry of the human body. These biochemical changes are detectable in metabolites. We employed global metabolomic profiling methods to screen biochemical changes that occur with mental fatigue in air traffic controllers (ATCs) in civil aviation. A total of 45, all male, ATCs (two batches) were recruited as two mental fatigue groups and 23 executive staff acted as a control group for this study. The volunteers' urine samples were collected before and after their work. The samples were analyzed with liquid chromatography/mass spectrometry equipped with a polar, a weak polar, and a nonpolar column, respectively. Three candidate biomarkers were selected on the basis of statistical significance, coefficient of variance, and compared with data of the three groups. The results suggest that urine metabolites may provide a complete new clue from biochemistry to understand, monitor, and manage human mental fatigue.

Serotonergic dysfunctions and abnormal iron metabolism: Relevant to mental fatigue of Parkinson disease.

Fatigue is a very common non-motor symptom in Parkinson disease (PD) patients. It included physical fatigue and mental fatigue. The potential mechanisms of mental fatigue involving serotonergic dysfunction and abnormal iron metabolism are still unknown. Therefore, we evaluated the fatigue symptoms, classified PD patients into fatigue group and non-fatigue group, and detected the levels of serotonin, iron and related proteins in CSF and serum. In CSF, 5-HT level is significantly decreased and the levels of iron and transferrin are dramatically increased in fatigue group. In fatigue group, mental fatigue score is negatively correlated with 5-HT level in CSF, and positively correlated with the scores of depression and excessive daytime sleepiness, and disease duration, also, mental fatigue is positively correlated with the levels of iron and transferrin in CSF. Transferrin level is negatively correlated with 5-HT level in CSF. In serum, the levels of 5-HT and transferrin are markedly decreased in fatigue group; mental fatigue score exhibits a negative correlation with 5-HT level. Thus serotonin dysfunction in both central and peripheral systems may be correlated with mental fatigue through abnormal iron metabolism. Depression, excessive daytime sleepiness and disease duration were the risk factors for mental fatigue of PD.

Feeling smart: Effects of caffeine and glucose on cognition, mood and self-judgment.

During education and early career, young adults often face examinations and assessment centers. Coffee and energy drinks are convenient and commonly used to enhance or maintain performance in these situations. Whether these macronutrients improve performance in a demanding and drawn-out multi-task situation is not clear. Using double-blind, placebo-controlled studies, we set out to examine the effects of caffeine and glucose in an assessment center-like situation, under natural consumption conditions, in a group of young adults who were heterogeneous with respect to consumption patterns. We measured multi-task performance including logical thinking, processing speed, numeric and verbal memory, attention and the ability to concentrate, and mood over a two-hour period. Caffeine and glucose were administered in common beverages with appropriate placebo controls allowing the assessment of psychological effects of expectancy. Importantly, and in contrast to most previous studies, participants retained their habitual caffeine and sugar intake (studies 1 and 2) as this represents common behavior. Based on the bulk of literature, we hypothesized that (i) caffeine enhances attentional performance and mood, while performance in more complex tasks will remain unchanged, and that (ii) glucose enhances performance on memory tasks accompanied with negative mood. Our results provide evidence that neither caffeine nor glucose significantly influence cognitive performance when compared with placebo, water, or no treatment controls in a multi-task setting. Yet, caffeine and, by trend, placebo improve dispositions such that participants perceive preserved mental energy throughout the test procedure. These subjective effects were stronger after 24 h caffeine abstinence (study 3). Future studies will have to address whether these mood changes actually result in increased motivation during a challenging task.

Chronic treatment with a tryptophan-rich protein hydrolysate improves emotional processing, mental energy levels and reaction time in middle-aged women.

Common pharmacological treatments of mood disorders aim to modulate serotonergic neurotransmission and enhance serotonin levels in the brain. Brain serotonin levels are dependent on the availability of its food-derived precursor essential amino acid tryptophan (Trp). We tested the hypothesis that delivery of Trp via food may serve as an alternative treatment, and examined the effects of a Trp-rich, bioavailable dietary supplement from egg protein hydrolysate on cognitive and emotional functions, mood state, and sleep quality. In a randomised, placebo-controlled, parallel trial, fifty-nine mentally and physically healthy women aged 45-65 years received placebo (n 30) or the supplement (n 29) (both as 0.5 g twice per d) for 19 d. Emotional processing was significantly changed by supplementation, exhibiting a shift in bias away from negative stimuli. The results for the Affective Go/No-Go Task exhibited a slowing of responses to negative words, suggesting reduced attention to negative emotional stimuli. The results for the Facial Emotional Expression Rating Task also supported a shift away from attention to negative emotions and a bias towards happiness. An increase in arousal-like symptoms, labelled 'high energy', shorter reaction times and a slight benefit to sustained attention were observed in the treated subjects. Finally, when the supplement was taken 60-90 min before bedtime, a feeling of happiness before going to bed was consistently reported. In summary, daily consumption of a low-dose supplement containing bioavailable Trp may have beneficial effects on emotional and cognitive functions.

In vivo ß-adrenergic receptor responsiveness: ethnic differences in the relationship with symptoms of depression and fatigue.

BACKGROUND: Depressive symptoms and fatigue frequently overlap in clinical samples and the general population. The link of depressive symptoms and fatigue with increased risk of cardiovascular disease has been partly explained by shared biological mechanisms including sympathetic overactivity. Prolonged sympathetic overactivity downregulates the responsiveness of the ß-adrenergic receptor (ß-AR), a receptor that mediates several end-organ sympathetic responses. PURPOSE: The authors studied whether depression and fatigue are related to reduced ß-AR responsiveness within the human body (in vivo) in an ethnically diverse sample of African and Caucasian Americans. METHODS: The chronotropic25 dose (CD25) was used to determine in vivo ß-AR responsiveness in 93 healthy participants. Psychometric measures included the Center of Epidemiological Studies-Depression Scale and the Multidimensional Fatigue Symptom Inventory. RESULTS: Hierarchical regression analyses (adjusted for age, gender, body mass index, blood pressure, smoking, and ethnicity) revealed that mental fatigue was significantly related to reduced ß-AR responsiveness (i.e., higher CD25 values) in the whole sample. Moderation analyses indicated significant ethnicity × depression/fatigue interactions. Depressive symptoms, total fatigue, emotional fatigue, mental fatigue, and physical fatigue were related to reduced ß-AR responsiveness in Caucasian American but not in African Americans. CONCLUSIONS: Our findings suggest that symptoms of depression and fatigue are related to decreased in vivo ß-AR responsiveness in Caucasian Americans. The lack of this association in African Americans highlights the importance for considering ethnicity as a potential moderator in research focusing on associations between psychological variables and cardiovascular function.

[Cytoprotectors and their application in sports medicine].

The article presents data of literature review on potential use of cytoprotectors in sports medicine (exemplified by Mildronat medication). This group of medications improve metabolism and energy supply in tissues. One of leading indications to Mildronat use is state of low mental and physical performance, including that of athletes.

Twenty-five years of research on the behavioural malaise associated with influenza and the common cold.

Minor illnesses such as the common cold and influenza are frequent and widespread. As well as specific symptoms such as nasal problems and fever, these illnesses are associated with a behavioural malaise. One feature of this malaise is reduced alertness and this has been confirmed using subjective reports and objective measures of performance. Such effects have been obtained with both experimentally induced infections and in studies of naturally occurring illnesses. The mechanisms underlying the effects are unclear but possibly reflect effects of cytokines on the CNS which result in changes in neurotransmitter functioning that lead to reduced alertness. The malaise induced by these illnesses has many real-life consequences and activities such as driving and safety at work may be at risk. These illnesses not only have direct effects on performance and mood but also make the person more sensitive to effects of other negative influences such as noise, alcohol and prolonged work. Countermeasures include ingestion of caffeine and other drugs known to increase alertness.

Dopaminergic involvement during mental fatigue in health and cocaine addiction.

Dopamine modulates executive function, including sustaining cognitive control during mental fatigue. Using event-related functional magnetic resonance imaging (fMRI) during the color-word Stroop task, we aimed to model mental fatigue with repeated task exposures in 33 cocaine abusers and 20 healthy controls. During such mental fatigue (indicated by increased errors, and decreased post-error slowing and dorsal anterior cingulate response to error as a function of time-on-task), healthy individuals showed increased activity in the dopaminergic midbrain to error. Cocaine abusers, characterized by disrupted dopamine neurotransmission, showed an opposite pattern of response. This midbrain fMRI activity with repetition was further correlated with objective indices of endogenous motivation in all subjects: a state measure (task reaction time) and a trait measure (dopamine D2 receptor availability in caudate, as revealed by positron emission tomography data collected in a subset of this sample, which directly points to a contribution of dopamine to these results). In a second sample of 14 cocaine abusers and 15 controls, administration of an indirect dopamine agonist, methylphenidate, reversed these midbrain responses in both groups, possibly indicating normalization of response in cocaine abusers because of restoration of dopamine signaling but degradation of response in healthy controls owing to excessive dopamine signaling. Together, these multimodal imaging findings suggest a novel involvement of the dopaminergic midbrain in sustaining motivation during fatigue. This region might provide a useful target for strengthening self-control and/or endogenous motivation in addiction.

Changes in plasma and tissue amino acid levels in an animal model of complex fatigue.

OBJECTIVE: Fatigue can be classified as physical or mental, depending on its cause. In physical fatigue, changes in the plasma levels of some amino acids have been reported. However, complex fatigue, which is experienced in daily life, is a combination of physical and mental fatigue. We aimed to identify changes in amino acid levels in the plasma, skeletal muscle, liver, and brain in an animal model of complex fatigue. METHODS: Rats were kept in a cage filled with water to a height of 2.2 cm for 5 d. Because rats showed a reduction of body weight when the model was developed, we also included a food-restricted group showing a similar profile in weight reduction as the water-immersed rats. A non-treated control group was also included. RESULTS: Results indicated that levels of branched-chain amino acids (valine, leucine, and isoleucine) were increased in plasma (valine, leucine, and isoleucine; P < 0.01), skeletal muscle (valine, leucine, and isoleucine; P < 0.01), the liver (valine; P < 0.05), and brain (isoleucine; P < 0.05), whereas a reduction in other amino acid levels (total amino acids and glutamine in the plasma, skeletal muscle, and liver; and phenylalanine, tyrosine, arginine, and threonine in the brain; P < 0.01) was seen in animals with complex fatigue. CONCLUSION: Complex fatigue may bring about systemic changes in amino acid metabolism in multiple organs.

Mental and physical fatigue-related biochemical alterations.

OBJECTIVE: To confirm fatigue-related biochemical alterations, we measured various parameters just before and after relaxation and fatigue-inducing mental or physical sessions. METHODS: Fifty-four healthy volunteers were randomized to perform relaxation and fatigue-inducing mental and physical sessions for 4 h in a double-blind, three-crossover design. Before and after each session, subjects were asked to rate their subjective sensations of fatigue, and blood, saliva, and urine samples were taken. RESULTS: After the fatigue-inducing mental and physical sessions, subjective scores of fatigue were increased. After the fatigue-inducing mental session, the vanillylmandelic acid level in urine was higher and plasma valine level was lower than after the relaxation session. In contrast, after the fatigue-inducing physical session, serum citric acid, triacylglycerol, free fatty acid, ketone bodies, total carnitine, acylcarnitine, uric acid, creatine kinase, aspartate aminotransferase, lactate dehydrogenase, cortisol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, plasma branched-chain amino acids, transforming growth factor-beta1 and -beta2, white blood cell and neutrophil counts, saliva cortisol and amylase, and urine vanillylmandelic acid levels were higher and serum free carnitine and plasma total amino acids and alanine levels were lower than those after the relaxation session. CONCLUSION: Some mental or physical fatigue-related biochemical changes were determined. Various biochemical alterations reflecting homeostatic perturbation and its responses might be shown. We believe that our results contribute to clarifying the mechanism of fatigue, developing evaluation methods, and establishing a basis for treatment.

Correlation of psychological and physical symptoms with chronically elevated cytokine levels associated with a common immune dysregulation.

BACKGROUND: Chronically elevated levels of proinflammatory cytokines are associated with inflammatory diseases and psychological symptoms of depression and tiredness. OBJECTIVE: To test the prediction that, in a healthy population without medically diagnosed diseases, psychological symptoms (depression and tiredness) associated with proinflammatory cytokines correlate with physical symptoms associated with inflammatory disease. METHODS: A total of 1,143 women between 45 and 65 years old completed a health complaint checklist containing 11 target symptoms (5 related to allergy, 4 to gastrointestinal symptoms, and 2 to pain), 7 control symptoms or health complaints, and 2 psychological symptoms (depression and tiredness). They also completed a menopausal quality-of-life questionnaire; to compensate for response bias, we removed variance attributable to quality of life. RESULTS: The partial correlations show that tiredness (but not depression) correlated with 9 of the 11 target symptoms (P < .001) but with 0 of the 7 control symptoms or complaints. Symptoms of both the specific and the systemic components of inflammatory disease are correlated in a healthy population. CONCLUSION: Immune dysregulation may explain the existence and covariation of psychological and physical symptoms in the healthy population, including people with medically unexplained symptoms.

Effects of beta-alanine supplementation on the onset of neuromuscular fatigue and ventilatory threshold in women.

This study examined the effects of 28 days of beta-alanine supplementation on the physical working capacity at fatigue threshold (PWCFT), ventilatory threshold (VT), maximal oxygen consumption (VO2-MAX), and time-to-exhaustion (TTE) in women. Twenty-two women (age+/-SD 27.4+/-6.1 yrs) participated and were randomly assigned to either the beta-alanine (CarnoSyn) or Placebo (PL) group. Before (pre) and after (post) the supplementation period, participants performed a continuous, incremental cycle ergometry test to exhaustion to determine the PWCFT, VT, VO2-MAX, and TTE. There was a 13.9, 12.6 and 2.5% increase (p<0.05) in VT, PWCFT, and TTE, respectively, for the beta-alanine group, with no changes in the PL (p>0.05). There were no changes for VO2-MAX (p>0.05) in either group. Results of this study indicate that beta-alanine supplementation delays the onset of neuromuscular fatigue (PWCFT) and the ventilatory threshold (VT) at submaximal workloads, and increase in TTE during maximal cycle ergometry performance. However, beta-alanine supplementation did not affect maximal aerobic power (VO2-MAX). In conclusion, beta-alanine supplementation appears to improve submaximal cycle ergometry performance and TTE in young women, perhaps as a result of an increased buffering capacity due to elevated muscle carnosine concentrations.

Relationship of energy metabolism detected by 31P-MRS in the human brain with mental fatigue.

To search for a possible relationship between brain energy metabolism and mental fatiguability, 10 normal volunteers were examined by 31P-MRS (phosphorus-31 magnetic resonance spectroscopy) in the occipital cortex during photic stimulation (PS), and Uchida-Kraepelin test (UKT), a standardized serial calculation task, was used for measurement of intraindividual characteristics of mental fatigue in these subjects. More decrease of phosphocreatine measured by 31P-MRS during the PS was significantly associated with more effects of rest assessed by UKT (r = -0.86, p <0.005). More decrease in pH after PS was associated with steeper decline of performance (r = 0.78, p <0.01). These findings suggest that characteristics of brain energy metabolism in an individual may relate to intrinsic patterns of mental fatigability.