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.

Dynamics in typewriting performance reflect mental fatigue during real-life office work.

Mental fatigue has repeatedly been associated with decline in task performance in controlled situations, such as the lab, and in less controlled settings, such as the working environment. Given that a large number of factors can influence the course of mental fatigue, it is challenging to objectively and unobtrusively monitor mental fatigue on the work floor. We aimed to provide a proof of principle of a method to monitor mental fatigue in an uncontrolled office environment, and to study how typewriting dynamics change over different time-scales (i.e., time-on-task, time-of-day, day-of-week). To investigate this, typewriting performance of university employees was recorded for 6 consecutive weeks, allowing not only to examine performance speed, but also providing a natural setting to study error correction. We show that markers derived from typewriting are susceptible to changes in behavior related to mental fatigue. In the morning, workers first maintain typing speed during prolonged task performance, which resulted in an increased number of typing errors they had to correct. During the day, they seemed to readjust this strategy, reflected in a decline in both typing speed and accuracy. Additionally, we found that on Mondays and Fridays, workers adopted a strategy that favored typing speed, while on the other days of the week typing accuracy was higher. Although workers are allowed to take breaks, mental fatigue builds up during the day. Day-to-day patterns show no increase in mental fatigue over days, indicating that office workers are able to recover from work-related demands after a working day.

How mental fatigue affects the neural sources of P300 component

Existence of allocentric and egocentric systems for human navigation, mediating spatial, and response learning, respectively, has so far been discussed. It is controversial whether navigational strategies and their underlying learning systems and, accordingly, the activation of their associated brain areas are independent/parallel or whether they functionally/causally interact in a competitive or in a cooperative manner to solve navigational tasks. The insights provided by neural networks involved in reward-based navigation attributed to individual involvement or interactions of learning systems have been surveyed. This paper characterizes the interactions of neural networks by constructing generative neural models and investigating their functional and effective connectivity patterns. A single-subject computer-based virtual reality environment was constructed to simulate a navigation task within a naturalistic large-scale space wherein participants were rewarded for using either a place, response, or mixed strategy at different navigational stages. First, functional analyses were undertaken to evaluate neural activities via mapping brain activation and making statistical inference. Effects of interest, spatial and response learning/retrieval, and their competition and cooperation were investigated. The optimal generative model was then estimated using dynamic casual modeling to quantify effective connectivities within the network. This analysis revealed how experimental conditions supported competition and cooperation strategies and how they modulated the underlying network. Results suggest that when navigational strategies cooperated, there were statistically significant, functional, and effective connectivities between hippocampus and striatum. However, when the strategies competed, effective connections were not established among these regions. Instead, connections between hippocampus/striatum and prefrontal cortex were strengthened. It can be inferred that a type of dynamical reconfiguration occurs within a network responsible for navigation when strategies interact either cooperatively or competitively. This supports adaptive causal organization of the brain when it is engaged with goal directed behavior.

On the role of the amygdala for experiencing fatigue in patients with multiple sclerosis.

BACKGROUND: Recently, we proposed a model explaining the origin of fatigue in multiple sclerosis (MS) patients. This model assumes that the feeling of fatigue results from inflammation-induced information processing within interoceptive brain areas. OBJECTIVES: To investigate the association between self-reported cognitive fatigue and structural integrity of interoceptive brain areas in MS patients. METHODS: 95 MS patients and 28 healthy controls participated in this study. All participants underwent diffusion tensor MRI and fractional anisotropy data were calculated for the amygdala, the stria terminalis and the corpus callosum, a non-interoceptive brain area. Based on the cognitive fatigue score of the Fatigue Scale for Motor and Cognition, patients were divided into moderately cognitively fatigued (cognitive fatigue score ≥ 28) and cognitively non-fatigued (cognitive fatigue score < 28) MS patients. Healthy controls were recruited as a third group. Repeated measures analyses of covariance, controlling for age, depression and brain atrophy, were performed to investigate whether the factor Group had a significant effect on the fractional anisotropy data. RESULTS: A significant effect of Group was observed for the amygdala (F = 3.389, p = 0.037). MS patients without cognitive fatigue presented lower values of the amygdala than MS patients with cognitive fatigue and healthy controls. For the stria terminalis and the corpus callosum, no main effect of Group was observed. CONCLUSION: The structural integrity of the amygdala in non-fatigued MS patients appears to be reduced. According to our model this might indicate that the absence of fatigue in non-fatigued MS patients might result from disturbed inflammation-induced information processing in the amygdala.

Cognitive fatigue is associated with reduced anterior internal capsule integrity in veterans with history of mild to moderate traumatic brain injury.

No known studies have directly examined white matter microstructural correlates of cognitive fatigue post-TBI in a Veteran sample. We therefore investigated the relationship between cognitive fatigue and white matter integrity in Veterans with history of mild to moderate TBI (mmTBI). 59 Veterans (TBI = 34, Veteran Controls [VCs] = 25]) with and without history of mmTBI underwent structural 3T DTI scans and completed questionnaires related to cognitive fatigue and psychiatric symptoms. Tractography was employed on six regions of interest, including the anterior and posterior limbs of the internal capsule; genu; body and splenium of the corpus callosum; and cingulum bundle. Group analyses revealed that those with history of mmTBI displayed significantly greater levels of cognitive fatigue relative to those with no history of head injury (p = .02). Within the mmTBI group, independent of psychiatric symptoms, decreased white matter microstructural integrity of the left anterior internal capsule was associated with greater levels of cognitive fatigue (p = .01). Results show that the subjective experience of cognitive fatigue following neurotrauma may be linked to the disruption of striato-thalamo-cortical tracts that are important in mediating arousal and higher-order cognitive processes. These findings build upon those from existing functional neuroimaging studies in those with history of TBI, providing further evidence for the neural basis of cognitive fatigue in head injured adults.

Time-frequency distribution properties of event-related potentials in mental fatigue induced by visual memory tasks.

Prolonged periods of demanding cognitive tasks lead to an exhausted feeling known as mental fatigue. The neural underpinnings of mental fatigue are still under exploration. In the present study, we aimed to identify neurophysiological indicators of mental fatigue by studying the time-frequency distribution of the event-related potentials (ERPs) measured in N=26 adults in nonfatigued versus fatigued states. We were interested in the frontal theta and occipital alpha variations, which have shown consistent relationships with mental fatigue in previous studies. Furthermore, we expected differential changes in left and right electrodes, in line with previously detected lateralization effects in cognitive tasks. Mental fatigue was induced by a sustained two-back verbal visual memory task for 125 min and assessed using the Chalder Fatigue Scale. We applied a high-resolution time-frequency analysis method called smoothed pseudo Wigner Ville distribution and used regional integrals as indicators for changing trends of signal energy. Results showed an increase in ERP frontal theta energy (P=0.03) and a decrease in occipital alpha energy (P=0.028) when participants became mentally fatigued. The change in frontal theta was more pronounced in left electrode sites (P=0.032), hinting toward a differential fatigue effect in the two hemispheres. The results were discussed on the basis of previous lateralization studies with memory tasks and interpreted as an indicator of a causal relationship between the sustained task execution and the physiological changes. Our findings also suggest that the ERP signal energy variations in frontal theta and occipital alpha might be used as neural biomarkers to assess mental fatigue.

On the relation between self-reported cognitive fatigue and the posterior hypothalamic-brainstem network.

BACKGROUND AND PURPOSE: Various causes have been suggested for multiple sclerosis (MS) related fatigue. Hypothalamus-brainstem fibres play a role in sleep-wake regulation and in hypothalamic deactivation during inflammatory states. Hence, they may play a role for experiencing fatigue by changing bottom-up hypothalamic activation. METHODS: Multiple sclerosis patients with and without self-reported cognitive fatigue and healthy controls were analysed with respect to the integrity of hypothalamus-brainstem fibres using diffusion-tensor imaging based tractography, focusing on the anterior, medial and posterior hypothalamic areas, controlling for clinical impairment and excluding participants with depressive mood. RESULTS: Multiple sclerosis patients without self-reported cognitive fatigue showed increased axial and radial diffusivity levels specifically for fibres connecting the right posterior hypothalamus with the right locus coeruleus, but not for the medial hypothalamus and the corpus callosum. Moreover, there were no differences between MS patients with and without fatigue in brain atrophy and lesion load, which could explain our results. CONCLUSION: Multiple sclerosis patients not experiencing fatigue show increased axial and radial diffusivity for fibres connecting the posterior hypothalamus and the brainstem, which might prevent bottom-up activation of the posterior hypothalamus and therefore downregulation of structures responsible for wakefulness and exploratory states of mind.

Neural effect of mental fatigue on physical fatigue: a magnetoencephalography study.

We sought to clarify the neural effect of mental fatigue on physical fatigue using magnetoencephalography (MEG) and classical conditioning techniques. Eleven right-handed volunteers participated in this study. On the first day, participants performed fatigue-inducing maximum handgrip trials for 10 min; metronome sounds were started 5 min after the beginning of the trials. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause physical fatigue. On the next day, MEG recordings during the imagery of maximum grips of the right hand guided by the metronome sounds were performed for 10 min just before (control session) and after (mental fatigue session) a 30-min fatigue-inducing mental task session. In the right anterior cingulate cortex (Brodmann's area 23), the alpha-band event-related synchronization of the mental fatigue session relative to the control session within the time window of 500­600 ms after the onset of handgrip cue sounds was identified. We demonstrated that mental fatigue suppresses activities in the right anterior cingulate cortex during physical fatigue.

Working memory in middle-aged males: age-related brain activation changes and cognitive fatigue effects.

We examined the effects of aging and cognitive fatigue on working memory (WM) related brain activation using functional magnetic resonance imaging. Age-related differences were investigated in 13 young and 16 middle-aged male school teachers. Cognitive fatigue was induced by sustained performance on cognitively demanding tasks (compared to a control condition). Results showed a main effect of age on left dorsolateral prefrontal and superior parietal cortex activation during WM encoding; greater activation was evident in middle-aged than young adults regardless of WM load or fatigue condition. An interaction effect was found in the dorsomedial prefrontal cortex (DMPFC); WM load-dependent activation was elevated in middle-aged compared to young in the control condition, but did not differ in the fatigue condition due to a reduction in activation in middle-aged in contrast to an increase in activation in the young group. These findings demonstrate age-related activation differences and differential effects of fatigue on activation in young and middle-aged adults.

Frontal theta activity reflects distinct aspects of mental fatigue.

Longer lasting performance in cognitively demanding tasks leads to an exhaustion of cognitive resources and to a state commonly described as mental fatigue. More specifically, the allocation and focusing of attention become less efficient with time on task. Additionally, the selection of even simple responses becomes more error prone. With respect to the recorded EEG, mental fatigue has been reported to be associated with an increase in frontal theta and frontal and occipital alpha activity. The present study focused on the time course of changes in behavior and in the EEG to characterize fatigue-related processes. Participants performed a spatial stimulus-response-compatibility task in eight blocks for an overall duration of 4h. Error rates increased continuously with time on task. Total alpha power was larger at the end compared to the beginning of the experiment. However, alpha power increased rapidly and reached its maximal amplitude already after 1h, whereas frontal theta showed a continuous increase with time on task, possibly related to increased effort to keep the performance level high. Time frequency analyses revealed power changes in the theta band induced by task relevant information that might be assigned to a drain of executive control capacities. Thus, frontal theta turned out to be a reliable marker of distinct changes in cognitive processing with increasing fatigue.

Mental fatigue and working memory load estimation: interaction and implications for EEG-based passive BCI.

Current mental state monitoring systems, a.k.a. passive brain-computer interfaces (pBCI), allow one to perform a real-time assessment of an operator's cognitive state. In EEG-based systems, typical measurements for workload level assessment are band power estimates in several frequency bands. Mental fatigue, arising from growing time-on-task (TOT), can significantly affect the distribution of these band power features. However, the impact of mental fatigue on workload (WKL) assessment has not yet been evaluated. With this paper we intend to help fill in this lack of knowledge by analyzing the influence of WKL and TOT on EEG band power features, as well as their interaction and its impact on classification performance. Twenty participants underwent an experiment that modulated both their WKL (low/high) and time spent on the task (short/long). Statistical analyses were performed on the EEG signals, behavioral and subjective data. They revealed opposite changes in alpha power distribution between WKL and TOT conditions, as well as a decrease in WKL level discriminability with increasing TOT in both number of statistical differences in band power and classification performance. Implications for pBCI systems and experimental protocol design are discussed.

Neural effects of prolonged mental fatigue: a magnetoencephalography study.

Mental fatigue, manifest as a reduced efficiency for mental work load, is prevalent in modern society. It is important to understand the neural mechanisms of mental fatigue and to develop appropriate methods for evaluating mental fatigue. In this study we quantified the effect of a long-duration mental fatigue-inducing task on neural activity. We used magnetoencephalography (MEG) to examine the time course change of neural activity over the long duration of the task trials. Nine healthy male volunteers participated in this study. They performed two mental fatigue-inducing tasks on separate days. The order of task presentation was randomized in a single-blinded, crossover fashion. Each task consisted of 25-min mental fatigue-inducing 0- or 2-back task session for three times. Subjective rating of mental fatigue sensation and electrocardiogram, and resting state MEG measurements were performed just before and after each task session. MEG data were analyzed using narrow-band adaptive spatial filtering methods. Alpha band (8-13 Hz) power in the visual cortex decreased after performing the mental fatigue-inducing tasks, and the decrease of alpha power was greater when they performed 2-back task trials. The decrease in alpha power was positively associated with the self-reported level of mental fatigue sensation and sympathetic nerve activity level. These results demonstrate that performing the prolonged mental fatigue-inducing task causes overactivation of the visual cortex, manifest as decreased alpha power in this brain region. Our results increase understanding of the neural mechanisms of mental fatigue and can be used to develop new quantitative methods to assess mental fatigue.

Astenia en pacientes que asisten a la consulta externa: valoración a través de la escala de intensidad de fatiga (FSS) / Asthenia in patients attending the outpatient clinic: valuation through the rating scale fatigue

Muchos pacientes acuden a consulta externa con un conjunto inespecífico de síntomas y signos que sugieren el diagnóstico de astenia, sin encontrarse una causa orgánica que explique dichos síntomas. Se realizó un estudio prospectivo a nivel nacional para diagnosticar y cuantificar la intensidad de la astenia en estos pacientes y medir la eficacia de la sulbutiamina 400 mg/día como tratamiento farmacológicoa corto plazo de primera línea. Se realizó un estudio abierto, prospectivo y multicéntrico,en el cual se ingresaron 341 pacientes, que consultaron ambulatoriamente y que presentaban síntomas de astenia. A través de la escala de Intensidad de Fatiga (por sus siglas en inglés: Fatigue Severity Scale - FSS) se determinó la presencia de astenia en estos pacientes y se evaluó la eficacia de la sulbutiamina 400 mg/día de Laboratorios Leti S.A.V., Venezuela (Tekron®). El estudio tuvo una duración de 15 días, en los cuales el paciente fue evaluado tres veces: día 1 (inicio), día 7 y día 15. Si el paciente presentaba astenia (puntuación ≥ 36 puntos en la FSS), se le indicaba sulbutiamina400 mg/día con el desayuno por 15 días. El 74,7% de los pacientes evaluados fueron del sexo femenino, con una edad media de 43,7 ± 12,5 años y el 25,3% del sexo masculino con una edad media de 41,7 ± 13,5 años. Al inicio del estudio la media de la puntuación de la FSS fue de 49,7 ± 7,3 puntos; a los 7 días de tratamiento con 400 mg/día de sulbutiamina fue de 37,2 ± 8,8 puntos con una disminucióndel 25,2% y al día 15 fue de 28,0 ± 9,8 puntos con una disminución de 43,7% con respecto al inicio del tratamiento, resultando estadísticamente significativo (p< 0,0001 y p< 0,0001 al día 7 y día 15 vs inicio, respectivamente). El 77,7% de los pacientes respondieron al tratamiento al día 15. La sulbutiamina resultó ser un tratamiento muy bien tolerado, se reportaron eventos adversos leves en 132 pacientes (38,7%) al día 7 y en 115 pacientes(33,7%) al día 15...

Many patients attending out patient clinics with a set of nonspecific symptoms and signs that suggest the diagnosis asthenia, without organic cause to explain the symptoms. In order to determine which of was these patients confirmed the diagnosis of functional asthenia, was performed a prospective nation wide, study to diagnose and quantify the intensity of fatigue in these patients and measure the effectiveness of sulbutiamine 400 mg/day treatment short-term drug frontline. Was realized an open, prospective, multicenter study, which entered 341 outpatient patients which showed signs of fati gue. The Fatigue Severity Scale (FSS) was used as a tool for the diagnosis and evaluation of severity of fatigue and was evaluated the effectiveness of sulbutiamine 400 mg/day to Leti Laboratories, S.A.V. (Tekron®), as first line treatment.The duration of the study was 15 days, with 3 evaluations (day 1 or baseline, day 7 and day 15). The score of the FSS had to be ≥ 36 points to be enrolled. 74,7% of patients were females with a mean age of 43,7 ± 12,5 years old and 25,3% were males with a mean age of 41,7 ± 13,5 years old. At baseline, the FSS score was 49,7 ± 7,3 points; at day 7 was 37,2 ± 8,8 points with a decrease of 25,2% and at day 15 was 28,0 ± 9,8 points, with a decrease of 43,7% respective to baseline, being statistically significant (p< 0,0001 and p< 0,0001 at day 7 and day 15, respectively). The percentage of response to treatment was 77,7% at day 15. Sulbutiamine was a very well tolerated treatment, there were reported mild adverse events in 132 patients (38,7%) at day 7 and in 115 patients (33,7%) at day 15. Sulbutiamine 400 mg/day is a secure treatment, it is well tolerated and effective in improving the asthenia symptoms, as demonstrated in this clinical trial by the significant decrease in the FSS mean score and the percentage of patients with asthenia at day 15 of treatment

Mental fatigue and impaired response processes: event-related brain potentials in a Go/NoGo task.

The effects of mental fatigue on the availability of cognitive resources and associated response-related processes were examined using event-related brain potentials. Subjects performed a Go/NoGo task for 60 min. Reaction time, number of errors, and mental fatigue scores all significantly increased with time spent on the task. The NoGo-P3 amplitude significantly decreased with time on task, but the Go-P3 amplitude was not modulated. The amplitude of error-related negativity (Ne/ERN) also decreased with time on task. These results indicate that mental fatigue attenuates resource allocation and error monitoring for NoGo stimuli. The Go- and NoGo-P3 latencies both increased with time on task, indicative of a delay in stimulus evaluation time due to mental fatigue. NoGo-N2 latency increased with time on task, but NoGo-N2 amplitude was not modulated. The amplitude of response-locked lateralized readiness potential (LRP) significantly decreased with time on task. Mental fatigue appears to slows down the time course of response inhibition, and impairs the intensity of response execution.

Mental fatigue: costs and benefits.

A framework for mental fatigue is proposed, that involves an integrated evaluation of both expected rewards and energetical costs associated with continued performance. Adequate evaluation of predicted rewards and potential risks of actions is essential for successful adaptive behaviour. However, while both rewards and punishments can motivate to engage in activities, both types of motivated behaviour are associated with energetical costs. We will review findings that suggest that the nucleus accumbens, orbitofrontal cortex, amygdala, insula and anterior cingulate cortex are involved evaluating both the potential rewards associated with performing a task, as well as assessing the energetical demands involved in task performance. Behaviour will only proceed if this evaluation turns out favourably towards spending (additional) energy. We propose that this evaluation of predicted rewards and energetical costs is central to the phenomenon of mental fatigue: people will no longer be motivated to engage in task performance when energetical costs are perceived to outweigh predicted rewards.

Mental fatigue alters the pattern and increases the volume of cerebral activation required for a motor task in multiple sclerosis patients with fatigue.

Fatigue is one of the most disabling symptoms in multiple sclerosis (MS) and there is increasing evidence it has a central origin. Our aim was to assess the impact of mental fatigue on motor task-related cerebral activation. Ten relapsing-remitting MS patients with fatigue were recruited and compared with seven controls. Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed a finger-thumb apposition task. The Paced-Auditory-Serial Addition Task (PASAT) was administered to induce fatigue and the fMRI motor paradigm was then repeated. Our results revealed that the PASAT altered the MS patients' activation patterns on the motor task. After the mentally fatiguing PASAT task, repeating the motor task was associated with patients recruiting significantly more of their brain including bilateral cingulate gyri and left primary sensory cortex, while activating less of the left premotor and supplementary motor area. The control subjects decreased their level of activation after the PASAT. Our current results reveal that a challenging mental task can alter the pattern and increase the volume of cerebral activation on an unrelated motor task in fatigued MS patients. These data support the hypothesis that a substrate for MS fatigue could be a generally elevated demand placed on functioning neural circuits.

Fatigue in the executive cortical network demonstrated in narcoleptics using functional magnetic resonance imaging--a preliminary study.

BACKGROUND AND PURPOSE: To demonstrate dynamic changes in cerebral functional activation during a working memory task in a state of severe excessive daytime sleepiness. PATIENTS AND METHODS: Omitting the usual morning dose of stimulants in three narcoleptics induced sleepiness. Functional magnetic resonance imaging (fMRI) was used to map cerebral activation during the performance of a 2-back verbal working memory task. Repeated 9.5 min scans were performed, until the subjects felt they could not continue. This was the functional imaging equivalent of the maintenance of wakefulness test. RESULTS: Bilateral and widespread activation in known nodes of the executive network were seen during the first scan in all subjects, including the lateral prefrontal, posterior parietal and anterior cingulate cortex. There was a reduction in cerebral activation, especially but not exclusively in the prefrontal cortex, associated with slowing of performance from the first to the last tolerated scan. On stimulants, subjective alertness, activation and objective performance were readily maintained. CONCLUSION: This preliminary study suggests that fatigue in the executive cortical network may be demonstrated by a progressive reduction in regional cerebral activation across scans, which may be prevented by stimulant use. Averaging multiple scan runs, a typical practice in fMRI, could blur important dynamic components of activation.