Decoding Post-Viral Fatigue: The Basal Ganglia's Complex Role in Long-COVID.

Long-COVID afflicts millions with relentless fatigue, disrupting daily life. The objective of this narrative review is to synthesize current evidence on the role of the basal ganglia in long-COVID fatigue, discuss potential mechanisms, and highlight promising therapeutic interventions. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases. Mounting evidence from PET, MRI, and functional connectivity data reveals basal ganglia disturbances in long-COVID exhaustion, including inflammation, metabolic disruption, volume changes, and network alterations focused on striatal dopamine circuitry regulating motivation. Theories suggest inflammation-induced signaling disturbances could impede effort/reward valuation, disrupt cortical-subcortical motivational pathways, or diminish excitatory input to arousal centers, attenuating drive initiation. Recent therapeutic pilots targeting basal ganglia abnormalities show provisional efficacy. However, heterogeneous outcomes, inconsistent metrics, and perceived versus objective fatigue discrepancies temper insights. Despite the growing research, gaps remain in understanding the precise pathways linking basal ganglia dysfunction to fatigue and validating treatment efficacy. Further research is needed to advance understanding of the basal ganglia's contribution to long-COVID neurological sequelae and offer hope for improving function across the expanding affected population.

Revealing the Complexity of Fatigue: A Review of the Persistent Challenges and Promises of Artificial Intelligence.

Part I reviews persistent challenges obstructing progress in understanding complex fatigue's biology. Difficulties quantifying subjective symptoms, mapping multi-factorial mechanisms, accounting for individual variation, enabling invasive sensing, overcoming research/funding insularity, and more are discussed. Part II explores how emerging artificial intelligence and machine and deep learning techniques can help address limitations through pattern recognition of complex physiological signatures as more objective biomarkers, predictive modeling to capture individual differences, consolidation of disjointed findings via data mining, and simulation to explore interventions. Conversational agents like Claude and ChatGPT also have potential to accelerate human fatigue research, but they currently lack capacities for robust autonomous contributions. Envisioned is an innovation timeline where synergistic application of enhanced neuroimaging, biosensors, closed-loop systems, and other advances combined with AI analytics could catalyze transformative progress in elucidating fatigue neural circuitry and treating associated conditions over the coming decades.

Artificial Intelligence's Transformative Role in Illuminating Brain Function in Long COVID Patients Using PET/FDG.

Cutting-edge brain imaging techniques, particularly positron emission tomography with Fluorodeoxyglucose (PET/FDG), are being used in conjunction with Artificial Intelligence (AI) to shed light on the neurological symptoms associated with Long COVID. AI, particularly deep learning algorithms such as convolutional neural networks (CNN) and generative adversarial networks (GAN), plays a transformative role in analyzing PET scans, identifying subtle metabolic changes, and offering a more comprehensive understanding of Long COVID's impact on the brain. It aids in early detection of abnormal brain metabolism patterns, enabling personalized treatment plans. Moreover, AI assists in predicting the progression of neurological symptoms, refining patient care, and accelerating Long COVID research. It can uncover new insights, identify biomarkers, and streamline drug discovery. Additionally, the application of AI extends to non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), which have shown promise in alleviating Long COVID symptoms. AI can optimize treatment protocols by analyzing neuroimaging data, predicting individual responses, and automating adjustments in real time. While the potential benefits are vast, ethical considerations and data privacy must be rigorously addressed. The synergy of AI and PET scans in Long COVID research offers hope in understanding and mitigating the complexities of this condition.

Effect of Post-COVID-19 on Brain Volume and Glucose Metabolism: Influence of Time Since Infection and Fatigue Status.

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.

Fatigue and perceived fatigability, not objective fatigability, are prevalent in people with post-COVID-19.

Persistent symptoms after acute COVID-19 infection, termed post-COVID-19 fatigue, occur in 44-70% of patients. Characterizing fatigue in this population is vital to determine the etiology of post-COVID-19 fatigue symptoms and to assess the effectiveness of potential interventions. The purpose of this study was to assess differences in perceived and objective fatigability between people with post-COVID-19 symptoms (N = 29, 20 females) and people who had COVID-19 but are not experiencing persistent symptoms (N = 20, 12 females). Perceived fatigability, fatigue, pain, and quality of life were assessed with the Fatigue Severity Scale (FSS), Fatigue Assessment Scale (FAS), Visual Analog Scale for Pain (VAS), and the EQ-5D-5L, respectively. Objective fatigability was evaluated with torque and work fatigue indices (FI-T and FI-W), calculated via an isokinetic fatigue task. The results revealed that, the subjects with post-COVID-19 symptoms had significantly higher FAS (p < 0.01), FSS (p < 0.01), VAS (p < 0.01), and EQ-5D-5L VAS (p < 0.01) scores compared to subjects without post-COVID-19 symptoms, indicating greater fatigue and perceived fatigability, increased pain, and worse quality of life. However, there were no differences between the two groups for the FI-Ts (all p ≥ 0.07) or FI-W (all p ≥ 0.08), indicating no differences in objective fatigability. This study found that people with post-COVID-19 symptoms have increased fatigue and perceived fatigability, but not objective fatigability, compared to subjects without post-COVID-19 symptoms.

Differences in Inhibitory Control and Resting Brain Metabolism between Older Chronic Users of Tetrahydrocannabinol (THC) or Cannabidiol (CBD)-A Pilot Study.

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.

Potential Factors That Contribute to Post-COVID-19 Fatigue in Women.

Mortality of acute coronavirus disease (COVID-19) is higher in men than in women. On the contrary, women experience more long-term consequences of the disease, such as fatigue. In this perspective article, we proposed a model of the potential factors that might contribute to the higher incidence of post-COVID-19 fatigue in women. Specifically, psycho-physiological factors are features that might increase central factors (e.g., inflammation) and result in greater perceptions of fatigue. Furthermore, pre-existing conditions likely play a prominent role. This model offers a framework for researchers and clinicians, and future research is required to validate our proposed model and elucidate all mechanisms of the increased incidence and prevalence of post-COVID-19 fatigue in women.

High Estrogen Levels Cause Greater Leg Muscle Fatigability in Eumenorrheic Young Women after 4 mA Transcranial Direct Current Stimulation.

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.

On the Effects of Transcranial Direct Current Stimulation on Cerebral Glucose Uptake During Walking: A Report of Three Patients With Multiple Sclerosis.

Common symptoms of multiple sclerosis (MS) include motor impairments of the lower extremities, particularly gait disturbances. Loss of balance and muscle weakness, representing some peripheral effects, have been shown to influence these symptoms, however, the individual role of cortical and subcortical structures in the central nervous system is still to be understood. Assessing [18F]fluorodeoxyglucose (FDG) uptake in the CNS can assess brain activity and is directly associated with regional neuronal activity. One potential modality to increase cortical excitability and improve motor function in patients with MS (PwMS) is transcranial direct current stimulation (tDCS). However, tDCS group outcomes may not mirror individual subject responses, which impedes our knowledge of the pathophysiology and management of diseases like MS. Three PwMS randomly received both 3 mA tDCS and SHAM targeting the motor cortex (M1) that controls the more-affected leg for 20 min on separate days before walking on a treadmill. The radiotracer, FDG, was injected at minute two of the 20 min walk and the subjects underwent a Positron emission tomography (PET) scan immediately after the task. Differences in relative regional metabolism of areas under the tDCS anode and the basal ganglia were calculated and investigated. The results indicated diverse and individualized responses in regions under the anode and consistent increases in some basal ganglia areas (e.g., caudate nucleus). Thus, anodal tDCS targeting the M1 that controls the more-affected leg of PwMS might be capable of affecting remote subcortical regions and modulating the activity (motor, cognitive, and behavioral functions) of the circuitry connected to these regions.

Sample entropy discriminates balance performance of older cannabis users from non-users.

BACKGROUND: Maintaining an upright stance involves a complex interaction of sensory processing and motor outputs to adequately perform this fundamental motor skill. Aging and cannabis use independently disrupt balance performance, but our recent data did not find differences in static balance performance between older cannabis Users and older Non-Users using traditional linear measures (i.e., characteristics of the center of pressure sway). The purpose of this analysis was to determine whether an unbiased entropy measure (sample entropy) can differentiate postural control (standing posture) strategies between older cannabis Users and Non-Users when typical linear measures could not. METHODS: Eight medical cannabis Users and eight age- and sex-matched controls completed static posturography testing in an eyes-open condition for 60 s. Linear measures included pathlength of the anterior-posterior and medio-lateral directions and an ellipse that encapsulates 95% of the 2D area explored. The nonlinear measure was the sample entropy of the center of pressure time-series in anterior-posterior and medio-lateral directions. Group comparisons were accomplished via pairwise testing and effect size calculations. FINDINGS: The statistical testing revealed that sample entropy in the anterior-posterior direction was significantly larger in the Users (mean ± SD = 0.29 ± 0.08) compared to the Non-Users (0.19 ± 0.05; P = 0.01, d = 1.55). INTERPRETATION: This finding indicates that the Users had a decreased regularity of their center of pressure signal in the anterior-posterior direction, which might reflect reduced balance adaptability and accompanies the increased fall risk observed in our recent report on these same subjects.

Cerebellar Contributions to Motor Impairments in People with Multiple Sclerosis.

Although Charcot characterized classic cerebellar symptoms in people with multiple sclerosis (PwMS) in 1877, the impact of cerebellar dysfunction on MS symptoms has predominately been evaluated in the last two decades. Recent studies have clearly demonstrated the association between cerebellar pathology, including atrophy and reduced fractional anisotropy in the peduncles, and motor impairments, such as reduced gait velocity and time to complete walking tasks. However, future studies using novel imaging techniques are needed to elucidate all potential pathophysiology that is associated with disability in PwMS. Additionally, future studies are required to determine the most effective treatments for motor impairments in PwMS, including the specific type and duration of exercise interventions, and potential means to amplify their effects, such as transcranial direct current stimulation (tDCS). This mini-review critically discusses the distinct role of cerebellar dysfunction in motor impairments in PwMS, potential treatments, and directions for future studies.

18F-FDG-PET Imaging for Post-COVID-19 Brain and Skeletal Muscle Alterations.

Scientific evidence concerning the subacute and long-term effects of coronavirus disease 2019 (COVID-19) is on the rise. It has been established that infection by serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a systemic process that involves multiple organs. The complications and long-term consequences of COVID-19 are diverse and patients need a multidisciplinary treatment approach in the acute and post-acute stages of the disease. A significant proportion of COVID-19 patients experience neurological manifestations, some enduring for several months post-recovery. However, brain and skeletal muscle changes resultant from SARS CoV-2 infection remain largely unknown. Here, we provide a brief overview of the current knowledge, and usefulness, of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) to investigate brain and skeletal muscles changes in Post-COVID-19 patients with persistent symptoms. Furthermore, a brief discussion of future 18F-FDG-PET/CT applications that might advance the current knowledge of the pathogenesis of post-COVID-19 is also provided.

Alterations in Leg Muscle Glucose Uptake and Inter-Limb Asymmetry after a Single Session of tDCS in Four People with Multiple Sclerosis.

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.

Personal Protective Equipment Alters Leg Muscle Fatigability Independent of Transcranial Direct Current Stimulation: A Comparison with Pre-COVID-19 Pandemic Results.

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.

Transcranial Direct Current Stimulation as a Treatment Tool for Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) has been defined as a transient (<24 h) condition of confusion and/or loss of consciousness for less than 30 min after brain injury and can result in short- and long-term motor and cognitive impairments. Recent studies have documented the therapeutic potential of non-invasive neuromodulation techniques for the enhancement of cognitive and motor function in mTBI. Alongside repetitive transcranial magnetic stimulation (rTMS), the main technique used for this purpose is transcranial direct current stimulation (tDCS). The focus of this review was to provide a detailed, comprehensive (i.e., both cognitive and motor impairment) overview of the literature regarding therapeutic tDCS paradigms after mTBI. A publication search of the PubMed, Scopus, CINAHL, and PsycINFO databases was performed to identify records that applied tDCS in mTBI. The publication search yielded 14,422 records from all of the databases, however, only three met the inclusion criteria and were included in the final review. Based on the review, there is limited evidence of tDCS improving cognitive and motor performance. Surprisingly, there were only three studies that used tDCS in mTBI, which highlights an urgent need for more research to provide additional insights into ideal therapeutic brain targets and optimized stimulation parameters.

Increased Likelihood of Falling in Older Cannabis Users vs. Non-Users.

Cannabis is one of the most common drugs in the United States and is the third most prevalent substance consumed by adults aged 50 years and older. Normal aging is associated with physiological changes that make older adults vulnerable to impaired function and geriatric conditions (e.g., falls, cognitive impairment). However, the impact of medical cannabis use on fall risk in older adults remains unexplored. The purpose of this study was to investigate if cannabis use in older adults influences fall risk, cognitive function, and motor function. It was hypothesized that older chronic cannabis users would perform worse than non-users on gait, balance, and cognitive tests. Sixteen older adults, split into cannabis Users and age- and sex-matched Non-Users groups (n = 8/group), participated in the study. The results indicate a higher fall risk, worse one leg standing balance performance, and slower gait speed in Users vs. Non-Users. No significant differences in cognitive function were found. Thus, chronic cannabis use was purported to exacerbate the poorer balance control and slower gait velocity associated with normal aging. Future mechanistic (e.g., neuroimaging) investigations of the short- and long-term effects of using a variety of cannabis products (e.g., THC/CBD ratios, routes of administration) on cognitive function, motor function, and fall incidence in older adults are suggested.

Disparity between Perceptual Fall Risk and Physiological Fall Risk in Older Cannabis Users: A Pilot Study.

Aging is associated with cognitive decline and increased fall risk. Cognitive impairment is associated with cannabis use, which is increasing among older adults. Perceptual and physiological fall risk are discordant in some older adults, but whether cannabis use influences this association is unknown. The purpose of this study was to investigate possible disparities between perceptual and physiological fall risk in older cannabis users. Eight older medical cannabis users and eight sex- and age-matched non-users provided data on perceptual and physiological fall risk. Group differences were assessed, and perceptual fall risk was correlated with physiological fall risk. Perceptual risk and most of the physiological fall risk variables were equivalent between the groups. However, cannabis users performed significantly worse on unipedal stance than non-users. In addition, perceptual fall risk had weak correlations with physiological fall risk in the users (Spearman's rho = 0.17-0.41) and moderate-strong correlations in non-users (rho = -0.18-0.67). Cannabis users might have a discrepancy between perceptual and physiological fall risk. Because both concepts play a role in quality of life, identifying strategies to improve them may have significant benefits. Future studies investigating additional perceptual (e.g., cognition, fear of falling, depression, anxiety), physiological (e.g., more challenging static and dynamic balance conditions), and general fall risk are warranted.

Women report more severe sensations from 2 mA and 4 mA transcranial direct current stimulation than men.

Interest in transcranial direct current stimulation (tDCS) to alter cortical excitability, facilitate neural plasticity, and improve performance is increasing. Subjects often report temporary stimulation-related sensations, which might distract from the task being performed or compromise blinding. tDCS is also prone to high outcome irregularity and one potential variability source is the biological sex of the subject. The purpose of this study was to re-analyze existing tolerability data to ascertain any sex differences in sensation severity and blinding guesses from tDCS at 2 mA and 4 mA. Each subject underwent tDCS at three randomly ordered intensities (sham, 2 mA, 4 mA), reported the severity sensations experienced, and guessed which tDCS condition they underwent (blinding). Women reported higher sensation severities than men from 2 mA and 4 mA tDCS and higher severities with increasing intensity (sham < 2 mA < 4 mA). Men reported similar severities in all stimulation conditions. Both sexes distinguished sham from 2 mA and 4 mA, and neither were able to discriminate between 2 mA from 4 mA. This study highlights differences in severity reports between women and men and adds to the growing body of literature, indicating that current sham methodologies might be inadequate to maintain blinding.

Post-COVID-19 Fatigue: Potential Contributing Factors.

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.