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.

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.

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.

Manual dexterity and strength and in young adults with and without Attention-Deficit/Hyperactivity Disorder (ADHD).

Manual motor deficits are common in children with attention deficit/hyperactivity disorder (ADHD); however, it is unclear whether these impairments persist into adulthood. The aim of this study was to examine manual dexterity and strength in young adults with ADHD aged 18-25 years. Sixty-one individuals with confirmed ADHD and 56 adults without ADHD completed Purdue Pegboard tasks for manual dexterity and maximal hand- and pinch-grip tests for strength. In the Purdue Pegboard task, participants placed pins using the right, left, and both-hands, respectively. In addition, participants built assemblies using pins, washers, and collars with alternating hand movements. The results demonstrated that women without ADHD out-performed the other three groups in the right-hand, bimanual, and assembly PPB tasks. Both maximal hand strength tests demonstrated that men were stronger than women, but no differences were observed between adults with and without ADHD. The current findings suggest that adults with ADHD may have deficits in manual dexterity and tasks requiring bimanual coordination.

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.

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.

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.

Individual Cerebral Blood Flow Responses to Transcranial Direct Current Stimulation at Various Intensities.

Transcranial direct current stimulation (tDCS) has been shown to alter cortical excitability. However, it is increasingly accepted that tDCS has high inter- and intra-subject response variability, which currently limits broad application and has prompted some to doubt if the current can reach the brain. This study reports individual cerebral blood flow responses in people with multiple sclerosis and neurologically healthy subjects that experienced 5 min of anodal tDCS at 1 mA, 2 mA, 3 mA, and 4 mA over either the dorsolateral prefrontal cortex (DLPFC) or the primary motor cortex (M1). The most notable results indicated anticipated changes in regional cerebral blood flow (rCBF) in two regions of one DLPFC subject (2 mA condition), and expected changes in one M1 subject in the 2 mA and 4 mA conditions and in another M1 subject in the 2 mA condition. There were also changes contrary to the expected direction in one DLPFC subject and in two M1 subjects. These data suggest the effects of tDCS might be site-specific and highlight the high variability and individualized responses increasingly reported in tDCS literature. Future studies should use longer stimulation durations and image at various time points after stimulation cessation when exploring the effects of tDCS on cerebral blood flow (CBF).

Different Effects of Transcranial Direct Current Stimulation on Leg Muscle Glucose Uptake Asymmetry in Two Women with Multiple Sclerosis.

Asymmetrical lower limb strength is a significant contributor to impaired walking abilities in people with multiple sclerosis (PwMS). Transcranial direct current stimulation (tDCS) may be an effective technique to enhance cortical excitability and increase neural drive to more-affected lower limbs. A sham-controlled, randomized, cross-over design was employed. Two women with MS underwent two 20 min sessions of either 3 mA tDCS or Sham before 20 min of treadmill walking at a self-selected speed. During walking, the participants were injected with the glucose analogue, [18F] fluorodeoxyglucose (FDG). Participants were then imaged to examine glucose metabolism and uptake asymmetries in the legs. Standardized uptake values (SUVs) were compared between the legs and asymmetry indices were calculated. Subject 2 was considered physically active (self-reported participating in at least 30 min of moderate-intensity physical activity on at least three days of the week for the last three months), while Subject 1 was physically inactive. In Subject 1, there was a decrease in SUVs at the left knee flexors, left upper leg, left and right plantar flexors, and left and right lower legs and SUVs in the knee extensors and dorsiflexors were considered symmetric after tDCS compared to Sham. Subject 2 showed an increase in SUVs at the left and right upper legs, right plantar flexors, and right lower leg with no muscle group changing asymmetry status. This study demonstrates that tDCS may increase neural drive to leg muscles and decrease glucose uptake during walking in PwMS with low physical activity levels.

Tolerability and Blinding of Transcranial Direct Current Stimulation in People with Parkinson's Disease: A Critical Review.

Transcranial direct current stimulation (tDCS) is accompanied by transient sensations (e.g., tingling, itching, burning), which may affect treatment outcomes or break the blinding of the study protocol. Assessing tolerability and blinding is integral to providing ample evidence of a "real effect" from the applied stimulation and dispelling the possibility of placebo effects. People with Parkinson's disease (PwPD) endure many motor and non-motor symptoms that might be amenable to tDCS. However, because the disease also affects sensation capabilities, these subjects might report tolerability and blinding differently than other cohorts. Therefore, the purpose of this review was to aggregate the tolerability and blinding reports of tDCS studies in PwPD and recommend a standard tolerability and blinding reporting practice. A literature search of the PubMed and Scopus databases from 1 January 2020 to 1 April 2020 was performed to identify publications that applied tDCS to PwPD. Seventy studies were potentially reviewable, but only 36 (nine with quantitative tolerability reports, 20 with qualitative tolerability reports, and seven that only reported blinding) provided sufficient information to be included in the review. Quantitative information on tDCS tolerability and blinding maintenance in PwPD is scarce, and future reviews and metanalyses should carefully consider the possibility of placebo effects in their included studies.

Different Effects of 2 mA and 4 mA Transcranial Direct Current Stimulation on Muscle Activity and Torque in a Maximal Isokinetic Fatigue Task.

Studies investigating the effects of transcranial direct current stimulation (tDCS) on fatigue and muscle activity have elicited measurable improvements using stimulation intensities ≤2 mA and submaximal effort tasks. The purpose of this study was to determine the effects of 2 mA and 4 mA anodal tDCS over the primary motor cortex (M1) on performance fatigability and electromyographic (EMG) activity of the leg muscles during a maximal isokinetic task in healthy young adults. A double-blind, randomized, sham-controlled crossover study design was applied. Twenty-seven active young adults completed four sessions, each spaced by 5-8 days. During session 1, dominance was verified with isokinetic strength testing, and subjects were familiarized with the fatigue task (FT). The FT protocol included 40 continuous maximum isokinetic contractions of the knee extensors and flexors (120°/s, concentric/concentric). During Sessions 2-4, tDCS was applied for 20 min with one of three randomly assigned intensities (sham, 2 mA or 4 mA) and the FT was repeated. The anode and cathode of the tDCS device were placed over C3 and the contralateral supraorbital area, respectively. A wireless EMG system collected muscle activity during the FT. The 2 mA tDCS condition had significantly less torque (65.9 ± 32.7 Nm) during the FT than both the sham (68.4 ± 33.9 Nm, p < 0.001) and 4 mA conditions (68.4 ± 33.9 Nm, p = 0.001). Furthermore, the 2 mA condition (33.8 ± 11.7%) had significantly less EMG activity during the FT than both the sham (39.7 ± 10.6%, p < 0.001) and 4 mA conditions (40.5 ± 13.4%, p = 0.001). Contrary to previous submaximal isometric fatigue investigations, the 2 mA tDCS condition significantly reduced torque production and EMG activity of the leg extensors during a maximal isokinetic FT compared with the sham and 4 mA conditions. Also, torque production and EMG activity in the 4 mA condition were not significantly different from sham. Thus, the effects of tDCS, and the underlying mechanisms, might not be the same for different tasks and warrants more investigation.

Transcranial Direct Current Stimulation at 4 mA Induces Greater Leg Muscle Fatigability in Women Compared to Men.

Transcranial direct current stimulation (tDCS) has previously shown different cortical excitability and neuropsychological effects between women and men. However, the sex-specific effects of tDCS on leg muscle fatigability has not been investigated. The purpose of this study was to determine the effects of a single session of 2 mA and 4 mA primary motor cortex tDCS on leg muscle fatigability in healthy young men and women in a crossover design. Twenty participants (women = 10) completed isokinetic fatigue testing (40 maximal reps, 120°/s) of the knee extensors and flexors in conjunction with sham, 2 mA, and 4 mA tDCS in a double-blind, randomized design. The fatigue index from each condition was calculated. Women had significantly greater knee extensor fatigability in the 4 mA condition compared to men (57.8 ± 6.8% versus 44.1 ± 18.4%; p = 0.041, d = 0.99). This study provides additional evidence that responses to tDCS may be sex-specific and highlights the necessity of accounting and powering for sex differences in future investigations.

Imaging Transcranial Direct Current Stimulation (tDCS) with Positron Emission Tomography (PET).

Transcranial direct current stimulation (tDCS) is a form of non-invasive neuromodulation that is increasingly being utilized to examine and modify several cognitive and motor functions. Although tDCS holds great potential, it is difficult to determine optimal treatment procedures to accommodate configurations, the complex shapes, and dramatic conductivity differences among various tissues. Furthermore, recent demonstrations showed that up to 75% of the tDCS current applied to rodents and human cadavers was shunted by the scalp, subcutaneous tissue, and muscle, bringing the effects of tDCS on the cortex into question. Consequently, it is essential to combine tDCS with human neuroimaging to complement animal and cadaver studies and clarify if and how tDCS can affect neural function. One viable approach is positron emission tomography (PET) imaging. PET has unique potential for examining the effects of tDCS within the central nervous system in vivo, including cerebral metabolism, neuroreceptor occupancy, and neurotransmitter activity/binding. The focus of this review is the emerging role of PET and potential PET radiotracers for studying tDCS-induced functional changes in the human brain.

Associations of lower limb joint asymmetry with fatigue and disability in people with multiple sclerosis.

BACKGROUND: An early symptom of multiple sclerosis is unilateral weakness, particularly in the lower limbs, which is associated with strength asymmetries. The purpose of this exploratory study was to examine strength asymmetries at the hip, knee, and ankle joints, and to investigate the associations between lower limb strength asymmetries and self-reported fatigue severity and disability in people with multiple sclerosis. METHODS: Sixteen mildly-disabled people with multiple sclerosis (females = 9) completed isokinetic maximal voluntary contractions of the hip extensors and flexors, knee extensors and flexors, and ankle plantar flexors and dorsiflexors. Asymmetry indices between the strength of the more- and less-affected lower limbs at each muscle group and the percent agreement between self-reported and objectively-determined more-affected lower limb were calculated. Patient Determined Diseases Steps and Fatigue Severity Scale were also completed. FINDINGS: All joints showed asymmetry (asymmetry indices ≥10%). Knee flexors (mean [SD]; 49.9 [37.8%]) and ankle plantar flexors (46.6 [35.5%]) had the largest asymmetry indices. Hip and knee extensors had the lowest asymmetry indices (21.1 [18.1%] and 30.1 [24.7%], respectively) and the highest agreement between self-reported and objectively-determined more-affected lower limb (93.3 and 93.8, respectively). The hip extensor asymmetry index was correlated with the Fatigue Severity Scale (r = 0.542, p = 0.037). INTERPRETATION: For the assessment of strength asymmetries in people with multiple sclerosis, it is suggested to 1) include measures of hip, knee, and ankle strength asymmetries, 2) include subjective perceptions and objective measures of strength asymmetries concurrently, and 3) to include measures of sensory function (proprioception).

Cerebellar Transcranial Direct Current Stimulation in People with Parkinson's Disease: A Pilot Study.

People with Parkinson's disease (PwPD) often experience gait and balance problems that substantially impact their quality of life. Pharmacological, surgical, and rehabilitative treatments have limited effectiveness and many PwPD continue to experience gait and balance impairment. Transcranial direct current stimulation (tDCS) may represent a viable therapeutic adjunct. The effects of lower intensity tDCS (2 mA) over frontal brain areas, in unilateral and bilateral montages, has previously been explored; however, the effects of lower and higher intensity cerebellar tDCS (2 mA and 4 mA, respectively) on gait and balance has not been investigated. Seven PwPD underwent five cerebellar tDCS conditions (sham, unilateral 2 mA, bilateral 2 mA, unilateral 4 mA, and bilateral 4 mA) for 20 min. After a 10 min rest, gait and balance were tested. The results indicated that the bilateral 4 mA cerebellar tDCS condition had a significantly higher Berg Balance Scale score compared to sham. This study provides preliminary evidence that a single session of tDCS over the cerebellum, using a bilateral configuration at a higher intensity (4 mA), significantly improved balance performance. This intensity and cerebellar configuration warrants future investigation in larger samples and over repeated sessions.