Much of the spotlight for coronavirus disease 2019 (COVID-19) is on the acute symptoms and recovery. However, many recovered patients face persistent physical, cognitive, and psychological symptoms well past the acute phase. Of these symptoms, fatigue is one of the most persistent and debilitating. In this “perspective article,” we define fatigue as the decrease in physical and/or mental performance that results from changes in central, psychological, and/or peripheral factors due to the COVID-19 disease and propose a model to explain potential factors contributing to post-COVID-19 fatigue. According to our model, fatigue is dependent on conditional and physiological factors. Conditional dependency comprises the task, environment, and physical and mental capacity of individuals, while physiological factors include central, psychological, and peripheral aspects. This model provides a framework for clinicians and researchers. However, future research is needed to validate our proposed model and elucidate all mechanisms of fatigue due to COVID-19.

Post-COVID-19 syndrome (PCS) fatigue is typically most severe <6 months post-infection. Combining magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging with the glucose analog [¹⁸F]-Fluorodeoxyglucose (FDG) provides a comprehensive overview of the effects of PCS on regional brain volumes and metabolism, respectively. The primary purpose of this exploratory study was to investigate differences in MRI/PET outcomes between people < 6 months (N = 18, 11 female) and > 6 months (N = 15, 6 female) after COVID-19. The secondary purpose was to assess if any differences in MRI/PET outcomes were associated with fatigue symptoms. Subjects > 6 months showed smaller volumes in the putamen, pallidum, and thalamus compared to subjects < 6 months. In subjects > 6 months, fatigued subjects had smaller volumes in frontal areas compared to non-fatigued subjects. Moreover, worse fatigue was associated with smaller volumes in several frontal areas in subjects > 6 months. The results revealed no brain metabolism differences between subjects > 6 and < 6 months. However, both groups exhibited both regional hypo- and hypermetabolism compared to a normative database. These results suggest that PCS may alter regional brain volumes but not metabolism in people > 6 months, particularly those experiencing fatigue symptoms.

Transcranial direct current stimulation (tDCS) research has shown great outcome variability in motor performance tasks, with one possible source being sex differences. The goal of this study was to evaluate the effects of estrogen levels on leg muscle fatigability during a fatigue task (FT) after 4 mA tDCS over the left motor cortex (M1). Ten young, healthy eumenorrheic women received 4 mA anodal active or sham stimulation over the left M1 during periods of high and low estrogen levels. A fatigue index (FI) was calculated to quantify fatigability, and the electromyography (EMG) of the knee extensors and flexors was recorded during the FT. The findings showed that tDCS applied during high estrogen levels resulted in greater leg muscle fatigability. Furthermore, a significant increase in EMG activity of the right knee extensors was observed during periods of active stimulation, independent of estrogen level. These results suggest that estrogen levels should be considered in tDCS studies with young healthy women.

Δ9-Tetrahydrocannabinol is the main psychoactive component of cannabis and cannabidiol is purportedly responsible for many of the medicinal benefits. The effects of Δ9-tetrahydrocannabinol and cannabidiol in younger populations have been well studied; however, motor function, cognitive function, and cerebral glucose metabolism in older adults have not been extensively researched. The purpose of this study was to assess differences in cognitive function, motor function, and cerebral glucose metabolism (assessed via [¹⁸F]-fluorodeoxyglucose positron emission tomography) in older adults chronically using Δ9-tetrahydrocannabinol, cannabidiol, and non-using controls. Eight Δ9-tetrahydrocannabinol users (59.3 ± 5.7 years), five cannabidiol users (54.6 ± 2.1 years), and 16 non-users (58.2 ± 16.9 years) participated. Subjects underwent resting scans and performed cognitive testing (reaction time, Flanker Inhibitory Control and Attention Test), motor testing (hand/arm function, gait), and balance testing. Δ9-tetrahydrocannabinol users performed worse than both cannabidiol users and non-users on the Flanker Test but were similar on all other cognitive and motor tasks. Δ9-tetrahydrocannabinol users also had lower global metabolism and relative hypermetabolism in the bilateral amygdala, cerebellum, and brainstem. Chronic use of Δ9-tetrahydrocannabinol in older adults might negatively influence inhibitory control and alter brain activity. Future longitudinal studies with larger sample sizes investigating multiple Δ9-tetrahydrocannabinol:cannabidiol ratios on functional outcomes and cerebral glucose metabolism in older adults are necessary.

Asymmetrical lower limb weakness is an early symptom and significant contributor to the progressive worsening of walking ability in people with multiple sclerosis (PwMS). Transcranial direct current stimulation (tDCS) may effectively increase neural drive to the more-affected lower limb and, therefore, increase symmetrical activation. Four PwMS (1 female, age range: 27–57) underwent one session each of 3 mA or SHAM tDCS over the motor cortex corresponding to their more-affected limb followed by 20 min of treadmill walking at a self-selected speed. Two min into the treadmill task, the subjects were injected with the glucose analog [¹⁸F]fluorodeoxyglucose (FDG). Immediately after treadmill walking, the subjects underwent whole-body positron emission tomography (PET) imaging. Glucose uptake (GU) values were compared between the legs, the spatial distribution of FDG was assessed to estimate glucose uptake heterogeneity (GUh), and GU asymmetry indices (AIs) were calculated. After tDCS, GU was altered, and GUh was decreased in various muscle groups in each subject. Additionally, AIs went from asymmetric to symmetric after tDCS in the subjects that demonstrated asymmetrical glucose uptake during SHAM. These results indicate that tDCS improved GU asymmetries, potentially from an increased neural drive and a more efficient muscle activation strategy of the lower limb in PwMS.

In response to the COVID-19 pandemic, the use of personal protective equipment (PPE; e.g., face mask) has increased. Mandating subjects to wear PPE during vigorous exercise might affect the fatigue outcomes of transcranial direct current stimulation (tDCS) studies. The purpose of this study was to investigate whether the use of PPE affected the performance of a tDCS-influenced fatigue task in healthy adults. A total of 16 young and healthy subjects were recruited and wore PPE during an isokinetic fatigue task in conjunction with sham, 2 mA, and 4 mA tDCS conditions. Subjects were matched to subjects who did not wear PPE during our previous pre-pandemic study in which right knee extensor fatigability increased under these same conditions. The results show that right knee extensor fatigability, derived from torque and work (FI-T and FI-W, respectively), was higher in the PPE study compared to the No PPE study in the sham condition. Additionally, there were no differences in knee extensor fatigability or muscle activity between sham, 2 mA, and 4 mA tDCS in the present study, which contrasts with our previous results. Thus, PPE worn by subjects and researchers might have a detrimental effect on fatigue outcomes in tDCS studies irrespective of the stimulation intervention.