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Abstract Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence (‘wearing-off’) before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab’s effect on MS-related fatigue. Forty-five relapsing–remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

Motor fatigue is one of the most common symptoms in multiple sclerosis (MS) patients. Previous studies suggested that increased motor fatigue in MS may arise at the central nervous system level. However, the mechanisms underlying central motor fatigue in MS are still unclear.This paper investigated whether central motor fatigue in MS reflects impaired corticospinal transmission or suboptimal primary motor cortex (M1) output (supraspinal fatigue). Furthermore, we sought to identify whether central motor fatigue is associated with abnormal M1 excitability and connectivity within the sensorimotor network.Twenty-two patients affected by relapsing-remitting MS and 15 healthy controls (HCs) performed repeated blocks of contraction at different percentages of maximal voluntary contraction with the right first dorsal interosseus muscle until exhaustion. Peripheral, central, and supraspinal components of motor fatigue were quantified by a neuromuscular assessment based on the superimposed twitch evoked by peripheral nerve and transcranial magnetic stimulation (TMS). Corticospinal transmission, excitability and inhibition during the task were tested by measurement of motor evoked potential (MEP) latency, amplitude, and cortical silent period (CSP). M1 excitability and connectivity was measured by TMS-evoked electroencephalography (EEG) potentials (TEPs) elicited by M1 stimulation before and after the task.Patients completed fewer blocks of contraction and showed higher values of central and supraspinal fatigue than HCs. We found no MEP or CSP differences between MS patients and HCs. Patients showed a post-fatigue increase in TEPs propagation from M1 to the rest of the cortex and in source-reconstructed activity within the sensorimotor network, in contrast to the reduction observed in HCs. Post-fatigue increase in source-reconstructed TEPs correlated with supraspinal fatigue values.To conclude, MS-related motor fatigue is caused by central mechanisms related explicitly to suboptimal M1 output rather than impaired corticospinal transmission. Furthermore, by adopting a TMS-EEG approach, we proved that suboptimal M1 output in MS patients is associated with abnormal task-related modulation of M1 connectivity within the sensorimotor network. Our findings shed new light on the central mechanisms of motor fatigue in MS by highlighting a possible role of abnormal sensorimotor network dynamics. These novel results may point to new therapeutical targets for fatigue in MS.

Abstract Background The aim of the current study was to examine multiple gait parameters obtained by wearable inertial sensors and their sensitivity to clinical status in early multiple sclerosis (MS). Further, a potential correlation between gait parameters and subjective fatigue was explored. Methods Automated gait analyses were carried out on 88 MS patients and 31 healthy participants. To measure gait parameters (i.e. walking speed, stride length, stride duration, duration of stance and swing phase, minimal toe-to-floor distance), wearable inertial sensors were utilized throughout a 6-min 25-ft walk. Additionally, self-reported subjective fatigue was assessed. Results Mean gait parameters consistently revealed significant differences between healthy participants and MS patients from as early as an Expanded Disability Status Scale (EDSS) value of 1.5 onwards. Further, MS patients showed a significant linear trend in all parameters, reflecting continuously deteriorating gait performance throughout the test. This linear deterioration trend showed significant correlations with fatigue. Conclusions Wearable inertial sensors are highly sensitive in the detection of gait disturbances, even in early MS, where global scales such as the EDSS do not provide any clinical information about deviations in gait behavior. Moreover, these measures provide a linear trend parameter of gait deterioration that may serve as a surrogate marker of fatigue. In sum, these results suggest that classic timed walking tests in routine clinical practice should be replaced by readily and automatically applicable gait assessments, as provided by inertial sensors.

Multiple Sclerosis (MS) is a heterogeneous immune mediated disease of the central nervous system (CNS). Fatigue is one of the most common and disabling symptom of MS. It interferes with daily activities on the level of cognition and motor endurance. Motor fatigue can either result from lesions in cortical networks or motor pathways ("primary fatigue") or it may be a consequence of detraining with subsequent adaptions of muscle and autonomic function. Programmed exercise interventions are used frequently to increase physical fitness in MS-patients. Studies investigating the effects of training on aerobic capacity, objective endurance and perceived fatigability have yielded heterogenous results, most likely due to the heterogeneity of interventions and patients, but probably also due to the non-uniform pathophysiology of fatigability among MS-patients. The aim of this review is to summarize the current knowledge on the pathophysiology of motor fatigability with special reference to the basic exercise physiology that underlies our understanding of both pathogenesis and treatment interventions. [ABSTRACT FROM AUTHOR]

ObjectivesFatigue is a frequent and often disabling symptom in patients with post-COVID syndrome. To better understand and evaluate the symptom of motor fatigue in the context of the post-COVID syndrome, we conducted treadmill walking tests to detect the phenomenon of motor fatigability or to evaluate whether evidence of organic lesions of the motor system could be found, similar to patients with multiple sclerosis.MethodTwenty-nine non-hospitalized patients with post-COVID syndrome completed the Fatigue Scale for Motor and Cognitive Function (FSMC) questionnaire to determine the trait component of subjective fatigue before they were tested on a treadmill walking at a moderate speed for up to 60 min or until exhaustion. During the walking test oxygen uptake, ventilation and acceleration data of both feet were collected. To determine motor performance fatigability, the Fatigue Index Kliniken Schmieder (FKS) was calculated using the attractor method.ResultsThe average walking duration was 42.7 ± 18.6 min with 15 subjects stopping the walking test prematurely. The FSMC score revealed a severe cognitive (37.6 ± 8.2) and motor (37.1 ± 7.8) fatigue averaged over all subjects but only two subjects showed an FKS above the normal range (>4), representing performance fatigability. There was no significant correlation between subjective fatigue (FSMC) and FKS as well as walking time. Absolute values of oxygen uptake and ventilation were in the normal range reported in literature (r = 0.9, p < 0.05), although eight subjects did not produce a steady-state behavior.ConclusionAlmost all patients with post-COVID syndrome and subjectively severe motor fatigue, did not show motor fatigability nor severe metabolic anomalies. This is argued against organic, permanent damage to the motor system, as is often seen in MS. Many of the patients were - to our and their own surprise - motorically more exertable than expected.

Multiple Sclerosis (MS) is a heterogeneous immune mediated disease of the central nervous system (CNS). Fatigue is one of the most common and disabling symptom of MS. It interferes with daily activities on the level of cognition and motor endurance. Motor fatigue can either result from lesions in cortical networks or motor pathways (“primary fatigue”) or it may be a consequence of detraining with subsequent adaptions of muscle and autonomic function. Programmed exercise interventions are used frequently to increase physical fitness in MS-patients. Studies investigating the effects of training on aerobic capacity, objective endurance and perceived fatigability have yielded heterogenous results, most likely due to the heterogeneity of interventions and patients, but probably also due to the non-uniform pathophysiology of fatigability among MS-patients. The aim of this review is to summarize the current knowledge on the pathophysiology of motor fatigability with special reference to the basic exercise physiology that underlies our understanding of both pathogenesis and treatment interventions.

Background: The aim of the current study was to examine multiple gait parameters obtained by wearable inertial sensors and their sensitivity to clinical status in early multiple sclerosis (MS). Further, a potential correlation between gait parameters and subjective fatigue was explored.Methods: Automated gait analyses were carried out on 88 MS patients and 31 healthy participants. To measure gait parameters (i.e. walking speed, stride length, stride duration, duration of stance and swing phase, minimal toe-to-floor distance), wearable inertial sensors were utilized throughout a 6-min 25-ft walk. Additionally, self-reported subjective fatigue was assessed.Results: Mean gait parameters consistently revealed significant differences between healthy participants and MS patients from as early as an Expanded Disability Status Scale (EDSS) value of 1.5 onwards. Further, MS patients showed a significant linear trend in all parameters, reflecting continuously deteriorating gait performance throughout the test. This linear deterioration trend showed significant correlations with fatigue.Conclusions: Wearable inertial sensors are highly sensitive in the detection of gait disturbances, even in early MS, where global scales such as the EDSS do not provide any clinical information about deviations in gait behavior. Moreover, these measures provide a linear trend parameter of gait deterioration that may serve as a surrogate marker of fatigue. In sum, these results suggest that classic timed walking tests in routine clinical practice should be replaced by readily and automatically applicable gait assessments, as provided by inertial sensors. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis is a chronic disease leading to reduced quality of life. Objectives: To investigate whether motor and cognitive fatigue impact differently on aspects of quality of life among patients with multiple sclerosis, independently from bodily disability. Methods: 79 patients with multiple sclerosis from Aalborg University Hospital, Denmark were included in an observational, cross-sectional study. Each subject completed two separate questionnaires regarding fatigue (Fatigue Scale for Motor and Cognitive Functions and Modified Fatigue Impact Scale) and one regarding quality of life (Short Form 36). Disability was measured with the Expanded Disability Status Scale (EDSS)-scores obtained from patient records. Results: All fatigue scores were significantly correlated to all areas of quality of life (p < 0,05). This remained significant after adjustment for age, disease duration and EDSS-score. When looking at each type of fatigue separately, cognitive fatigue correlated mainly with mental health aspects of quality of life and motor fatigue with physical health areas of quality of life. Conclusion: Increased motor and cognitive fatigue lead to a differential reduction in physical and mental quality of life, independently of bodily disability. This underlines the importance of proper assessment and treatment of fatigue among patients with multiple sclerosis. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is characterized by demyelination and neurodegeneration of the central nervous system and causes excessive fatigue in more than 80% of the patients. The pathophysiologic mechanisms causing fatigue are still largely unknown. In 46 right-handed patients with relapsing-remitting MS and 25 right-handed controls, we performed diffusion MRI and applied streamline based probabilistic tractography to derive unilateral anatomical connectivity maps for the white matter of the right and left hemispheres. The maps provide an indication how often a streamline has passed through a given voxel. Since tractography based anatomical connectivity mapping (ACM) is sensitive to disease-induced changes in anatomical connectivity, we used ACM to test whether motor fatigue is associated with altered ipsi-hemispherical anatomical connectivity in the major motor output pathway, the corticospinal tract (CST). Patients had higher mean ACM values in the CST than healthy controls. This indicated that a higher number of streamlines, starting from voxels in the same hemisphere, travelled through the CST and may reflect an accumulated disease-induced disintegration of CST. The motor subscale of the Fatigue Scale for Motor and Cognitive functions (FSMCMOTOR) was used to define sub-groups with (n = 29, FSMCMOTOR score ≥ 27) and without motor fatigue (n = 17, FSMSMOTOR score ≤ 26). Patients without fatigue only showed higher ACM values in right CST, while mean ACM values were unaltered in left CST. The higher the mean ACM values in the left relative to the right CST, the more patients reported motor fatigue. Left-right asymmetry in anatomical connectivity outside the CST did not scale with individual motor fatigue. Our results link lateralized changes of tractography-based microstructural properties in the CST with motor fatigue in relapsing-remitting MS.

Background: Altered balance/stability during walking is common in people with multiple sclerosis (PwMS). While dynamic gait stability has been related to falling and localized muscle fatigue, it has rarely been studied in MS. Specifically, the effects of walking-related fatigue on dynamic stability are unclear in PwMS.Research Questions: 1) Are temporal changes in dynamic stability during long-walks different among PwMS and healthy controls (HC)? 2) Is there a relationship between stability and walking performance changes in PwMS?Methods: Twenty-five PwMS and ten HC participated in the six-minute walk test (6MWT) wearing six-wireless inertial sensors. Local dynamic stability (LDS) during gait was quantified by maximum-finite-time Lyapunov exponents (λS), where larger λS indicates less stable dynamics. Linear mixed models were fit to compare changes in LDS and walking performance over time among two groups. Additionally, the percent changes in λS and distance from minute 1 to 6 were recorded as Dynamic Stability Index (DSI6-1) and Distance-Walked Index (DWI6-1) respectively. Finally, Pearson correlation compared the association between DSI6-1 and DWI6-1.Results: A significant group*time interaction was found for LDS. PwMS did not have different LDS than HC until minute-4 of walking, and differences persisted at minute-6. Further, PwMS walked significantly shorter distances and demonstrated a greater decline in walking performance (DWI6-1) during the 6MWT. Finally, DSI6-1 and DWI6-1 were significantly correlated in PwMS. Significance The dynamic stability differences among PwMS and HC were only apparent after 3-minutes of walking and ∼60% of PwMS became less stable over time, supporting the use of long walks in MS to capture stability changes during the motor task performance. A significant relationship between the decline in stability and poor walking performance over time during the 6MWT suggested a possible role of walking-related fatigue in the worsening of balance during long walks in PwMS. [ABSTRACT FROM AUTHOR]

To evaluate task induced motor fatigue in a well-established finger tapping task, we analyzed tapping parameters and included the time course of measures of force. We hypothesized that a decline in tapping force would reflect task induced motor fatigue, defined by a lengthening of inter-tap intervals (ITI). A secondary aim was to investigate the reliability of tapping data acquisition with the force sensor. Results show that, as expected, tapping speed decreased linearly over time, due to both an increase of ITI and tap duration. In contrast, tapping force increased non-linearly over time and was uncorrelated to changes in tapping speed. Force data could serve as a measure to characterize task induced motor fatigue. Force sensors can assess a decline in tapping speed as well as an independent increase of tapping force. We argue that the increase of force reflects central compensation, i.e. perception of fatigue, due to an increase in task effort and difficulty. [ABSTRACT FROM AUTHOR]

Background: Although the effects of mental fatigue on cognitive–motor function and psychological state in young adults are well-documented, its effects in the elderly are not completely understood. The aim of this study was to estimate the effect of prolonged cognitive load on the indicators of psychological, cognitive, and motor functions.Methods: Fifteen young and 15 elderly men were asked to perform a 2 h “Go/NoGo” task. Psychological state (mood and motivation), cognitive (prefrontal cortex activity and cognitive performance), and motor (motor cortex excitability and grip strength) functions were measured before and after the task. During the 2 h task, both groups had a significantly similar increase in the number of “Incorrect NoGo” errors. Only in young men reaction time (RT) of “Incorrect NoGo” and intraindividual variability of RT of “Incorrect NoGo” significantly increased during task. After the task, handgrip strength decreased for the young men, whereas latency of motor evoked potentials prolonged both groups. Nevertheless, both groups indicated that they felt fatigue after the 2 h task; we observed that mental demand increased, whereas intrinsic motivation and mood decreased only in young men. Prolonged task decreased the switching/rest ratio of oxygenated hemoglobin for the young and the elderly men; however, greater for elderly than young men. Interestingly, the more the prefrontal cortex was activated before the 2 h task during the switching task, the fewer of “Incorrect NoGo” errors made by the young men and the greater the number of errors made by the elderly men.Conclusion: Because of the greater mental load and (possibly) greater activation of prefrontal cortex during the 2 h “Go/NoGo” task, there was greater mental and neuromuscular performance fatigue in young men than in elderly men.

Background: Although the effects of mental fatigue on cognitive–motor function and psychological state in young adults are well-documented, its effects in the elderly are not completely understood. The aim of this study was to estimate the effect of prolonged cognitive load on the indicators of psychological, cognitive, and motor functions. Methods: Fifteen young and 15 elderly men were asked to perform a 2 h “Go/NoGo” task. Psychological state (mood and motivation), cognitive (prefrontal cortex activity and cognitive performance), and motor (motor cortex excitability and grip strength) functions were measured before and after the task. During the 2 h task, both groups had a significantly similar increase in the number of “Incorrect NoGo” errors. Only in young men reaction time (RT) of “Incorrect NoGo” and intraindividual variability of RT of “Incorrect NoGo” significantly increased during task. After the task, handgrip strength decreased for the young men, whereas latency of motor evoked potentials prolonged both groups. Nevertheless, both groups indicated that they felt fatigue after the 2 h task; we observed that mental demand increased, whereas intrinsic motivation and mood decreased only in young men. Prolonged task decreased the switching/rest ratio of oxygenated hemoglobin for the young and the elderly men; however, greater for elderly than young men. Interestingly, the more the prefrontal cortex was activated before the 2 h task during the switching task, the fewer of “Incorrect NoGo” errors made by the young men and the greater the number of errors made by the elderly men. Conclusion: Because of the greater mental load and (possibly) greater activation of prefrontal cortex during the 2 h “Go/NoGo” task, there was greater mental and neuromuscular performance fatigue in young men than in elderly men. [ABSTRACT FROM AUTHOR]

Background Motor fatigability is increasingly acknowledged in persons with MS (pwMS). It is unknown whether fatigability is generalized across upper limb muscles and relates to fatigue and perceived difficulties in upper limb use. Methods This observational case-controlled study included twenty PwMS (median EDSS = 3, range 1.5–6.5) and twenty healthy controls who performed 30″ sustained maximal muscle contractions for index finger abduction, hand grip, elbow flexion and shoulder abduction. A static fatigue index (SFI) was calculated to assess motor fatigability for each muscle group. PwMS completed the Fatigue Severity Scale (FSS) and Modified Fatigue Index Scale (MFIS), to quantify severity and perceived impact of fatigue and the Manual Ability Measure (MAM-36) reflecting perceived difficulty in using the upper limbs. Comparisons between groups and muscles was made by t -tests. Associations between outcomes were calculated with correlation coefficients. Results Fatigue was highest in pwMS. PwMS showed preserved muscle strength and a greater motor fatigability in elbow flexors compared to healthy controls. SFI of elbow flexors and shoulder abductors were associated, and contributed to FSS and MFIS. SFI of elbow flexors and finger abductors predicted half of the variation in MAM-36. Conclusion Increased motor fatigability was only present in elbow flexors of PwMS, indicating that expression of motor fatigability is not generalized. Fatigability was associated with perceived fatigue (impact) and daily life upper limb use. Results are preliminary given the small sample size with predominantly persons with mild MS. [ABSTRACT FROM AUTHOR]

Background. The aim of this study was to follow symptoms of exercise induced muscle damage in response to 50, 100 and 200 drop jumps with maximal intensity. Methods. Three groups of young healthy men (n = 10 in each group) performed a bout of mechanically demanding stretch shortening cycle exercise consisting of 50, 100 and 200 drop jumps. Voluntary and electrically induced knee extension torque, creatine kinase, muscle soreness were measured before and 24 h after exercise. Results. Indirect symptoms of exercise induced damage were dependent on DJs volume: the higher the numbers of jumps, the more symptoms were observed. Only after 200 DJs compared to 50-100 DJ there was decrease of CAR and H of DJ, and 24 h after 200 DJs CK was greater than after 50-100 DJs. Conclusion. In response to acute severe muscle-damaging exercise (after 200 DJs), indirect symptoms of exercise-induced muscle damage occurred. [ABSTRACT FROM AUTHOR]

Lower-body robotic exoskeletons can be used to reduce the energy demand of locomotion and increase the endurance of wearers. Understanding how motor fatigue affects walking performance may lead to better exoskeleton designs to support the changing physical capacity of an individual due to motor fatigue. The purpose of this study was to investigate the effects of motor fatigue on walking mechanics and energetics. Treadmill walking with progressively increased incline gradient was used to induce motor fatigue. Twenty healthy young participants walked on an instrumented treadmill at 1.25 m/s and 0° of incline for 5 min before (PRE) and after (POST) motor fatigue. We examined lower-limb joint mechanics, metabolic cost, and the efficiency of positive mechanical work (η+ work). Compared to PRE, participants had increased net metabolic power by ∼14% (p < 0.001) during POST. Participants also had increased total-limb positive mechanical power (Total P+ mech) by ∼4% during POST (p < 0.001), resulting in a reduced η+ work by ∼8% (p < 0.001). In addition, the positive mechanical work contribution of the lower-limb joints during POST was shifted from the ankle to the knee while the negative mechanical work contribution was shifted from the knee to the ankle (all p < 0.017). Although greater knee positive mechanical power was generated to compensate for the reduction in ankle positive power after motor fatigue, the disproportionate increase in metabolic cost resulted in a reduced walking efficiency. The findings of this study suggest that powering the ankle joint may help delay the onset of the lower-limb joint work redistribution observed during motor fatigue. [ABSTRACT FROM AUTHOR]

Motor fatigue is one of the most common symptoms in multiple sclerosis (MS) patients. Previous studies suggested that increased motor fatigue in MS may arise at the central nervous system level. However, the mechanisms underlying central motor fatigue in MS are still unclear. This paper investigated whether central motor fatigue in MS reflects impaired corticospinal transmission or suboptimal primary motor cortex (M1) output (supraspinal fatigue). Furthermore, we sought to identify whether central motor fatigue is associated with abnormal M1 excitability and connectivity within the sensorimotor network. Twenty-two patients affected by relapsing-remitting MS and 15 healthy controls (HCs) performed repeated blocks of contraction at different percentages of maximal voluntary contraction with the right first dorsal interosseus muscle until exhaustion. Peripheral, central, and supraspinal components of motor fatigue were quantified by a neuromuscular assessment based on the superimposed twitch evoked by peripheral nerve and transcranial magnetic stimulation (TMS). Corticospinal transmission, excitability and inhibition during the task were tested by measurement of motor evoked potential (MEP) latency, amplitude, and cortical silent period (CSP). M1 excitability and connectivity was measured by TMS-evoked electroencephalography (EEG) potentials (TEPs) elicited by M1 stimulation before and after the task. Patients completed fewer blocks of contraction and showed higher values of central and supraspinal fatigue than HCs. We found no MEP or CSP differences between MS patients and HCs. Patients showed a post-fatigue increase in TEPs propagation from M1 to the rest of the cortex and in source-reconstructed activity within the sensorimotor network, in contrast to the reduction observed in HCs. Post-fatigue increase in source-reconstructed TEPs correlated with supraspinal fatigue values. To conclude, MS-related motor fatigue is caused by central mechanisms related explicitly to suboptimal M1 output rather than impaired corticospinal transmission. Furthermore, by adopting a TMS-EEG approach, we proved that suboptimal M1 output in MS patients is associated with abnormal task-related modulation of M1 connectivity within the sensorimotor network. Our findings shed new light on the central mechanisms of motor fatigue in MS by highlighting a possible role of abnormal sensorimotor network dynamics. These novel results may point to new therapeutical targets for fatigue in MS. [Display omitted] • Motor fatigue in multiple sclerosis (MS) is not due to corticospinal mechanisms. • Motor fatigue in MS is due to a suboptimal M1 output. • Suboptimal M1 output in MS is associated with abnormal modulation of M1 connectivity. • Motor fatigue in MS reflects abnormal fatigue-related sensorimotor network changes. [ABSTRACT FROM AUTHOR]

One aspect of motor fatigue is the exercise-induced reduction of neural activity to voluntarily drive the muscle or muscle group. Functional magnetic resonance imaging provides access to investigate the neural activation on the whole brain level and studies observed changes of activation intensity after exercise-induced motor fatigue in the sensorimotor cortex. However, in human, little evidence exists to demonstrate the role of subcortical brain regions in motor fatigue, which is contradict to abundant researches in rodent indicating that during simple movement, the activity of the basal ganglia is modulated by the state of motor fatigue. Thus, in present study, we explored the effect of motor fatigue on subcortical areas in human. A series of fMRI data were collected from 11 healthy subjects while they were executing simple motor tasks in two conditions: before and under the motor fatigue state. The results showed that in both conditions, movements evoked activation volumes in the sensorimotor areas, SMA, cerebellum, thalamus and basal ganglia. Of primary importance are the results that the intensity and size of activation volumes in the subcortical areas (i.e. thalamus and basal ganglia areas) are significantly decreased during the motor fatigue state, implying that motor fatigue disturbs the motor control processing in a way that both sensorimotor areas and subcortical brain areas are less active. Further study is needed to clarify how subcortical areas contribute to the overall decreased activity of CNS during motor fatigue state.

Introduction During maximal, sustained contractions, persons with multiple sclerosis (PwMS) show higher motor fatigability in comparison with healthy persons. It is not known if motor fatigability is also different between PwMS and healthy persons during low-intensity exercises. Thus, the aim of this study was to determine the difference in hand grip fatigability between healthy persons and PwMS for both hands during low-intensity hand grip exercises. Methods 19 PwMS and 19 healthy controls performed 18 min of hand grip exercises at a maximum of 25% of the maximal voluntary strength, with an electronic hand dynamometer. Perceived fatigability, maximal hand grip strength and muscle activity (electromyography) of the wrist flexors and extensors were recorded in between these exercises for the dominant and non-dominant hand. Results and discussion There was a significant decrease in maximal hand grip strength after exercising in both groups and for both hands, mainly situated in the first 6 min. In contrast to what was hypothesized, PwMS did not show more decline in strength than healthy controls, neither in the dominant nor the non-dominant hand. There was no group difference in the increase of the perceived fatigability in the dominant hand. However, for the non-dominant hand, the perceived fatigability after exercising increased more in PwMS than in healthy controls. Additionally, there was no relation between fatigue indices, as assessed with short maximal contractions and the strength decline after low-intensity repetitive exercises. [ABSTRACT FROM AUTHOR]

One aspect of motor fatigue is the exercise-induced reduction of neural activity to voluntarily drive the muscle or muscle group. Functional magnetic resonance imaging provides access to investigate the neural activation on the whole brain level and studies observed changes of activation intensity after exercise-induced motor fatigue in the sensorimotor cortex. However, in human, little evidence exists to demonstrate the role of subcortical brain regions in motor fatigue, which is contradict to abundant researches in rodent indicating that during simple movement, the activity of the basal ganglia is modulated by the state of motor fatigue. Thus, in present study, we explored the effect of motor fatigue on subcortical areas in human. A series of fMRI data were collected from 11 healthy subjects while they were executing simple motor tasks in two conditions: before and under the motor fatigue state. The results showed that in both conditions, movements evoked activation volumes in the sensorimotor areas, SMA, cerebellum, thalamus, and basal ganglia. Of primary importance are the results that the intensity and size of activation volumes in the subcortical areas (i.e., thalamus and basal ganglia areas) are significantly decreased during the motor fatigue state, implying that motor fatigue disturbs the motor control processing in a way that both sensorimotor areas and subcortical brain areas are less active. Further study is needed to clarify how subcortical areas contribute to the overall decreased activity of CNS during motor fatigue state. [ABSTRACT FROM AUTHOR]

Fatigue is often reported in stroke patients. However, it is still unclear if fatigue in stroke patients is more prominent, more frequent or more typical than in patients with multiple sclerosis (MS) and if the pathophysiology differs between these two populations. The purpose of this study was to compare motor fatigue and fatigue induced changes in kinematic gait parameters between stroke patients, MS patients and healthy persons. Gait parameters at the beginning and end of a treadmill walking test were assessed in 10 stroke patients, 40 MS patients and 20 healthy subjects. The recently developed Fatigue index Kliniken Schmieder (FKS) based on change of the movement’s attractor and its variability was used to measure motor fatigue. Six stroke patients had a pathological FKS. The FKS (indicating the level of motor fatigue) in stroke patients was similar compared to MS patients. Stroke patients had smaller step length, step height and greater step width, circumduction with the right and left leg as well as greater sway compared to the other groups at the beginning and at the end of test. A severe walking impairment in stroke patients does not necessarily cause a pathological FKS indicating motor fatigue. Moreover, the FKS can be used as a measure of motor fatigue in stroke and MS and may also be applicable to other diseases.

Fatigue is often reported in stroke patients. However, it is still unclear if fatigue in stroke patients is more prominent, more frequent or more "typical" than in patients with multiple sclerosis (MS) and if the pathophysiology differs between these two populations. The purpose of this study was to compare motor fatigue and fatigue-induced changes in kinematic gait parameters between stroke patients, MS patients, and healthy persons. Gait parameters at the beginning and end of a treadmill walking test were assessed in 10 stroke patients, 40 MS patients, and 20 healthy subjects. The recently developed Fatigue index Kliniken Schmieder (FKS) based on change of the movement's attractor and its variability was used to measure motor fatigue. Six stroke patients had a pathological FKS. The FKS (indicating the level of motor fatigue) in stroke patients was similar compared to MS patients. Stroke patients had smaller step length, step height and greater step width, circumduction with the right and left leg, and greater sway compared to the other groups at the beginning and at the end of test. A severe walking impairment in stroke patients does not necessarily cause a pathological FKS indicating motor fatigue. Moreover, the FKS can be used as a measure of motor fatigue in stroke and MS and may also be applicable to other diseases. [ABSTRACT FROM AUTHOR]

The article examines the amount of sick leave in relapsing-remitting multiple sclerosis (RRMS) before and after one year of natalizumab treatment. It correlate the results of the study to fatigue and walking ability. It also evaluates the effect on multiple sclerosis (MS)-related fatigue after 12 months of treatment with natalizumab.

Purpose: Polio survivors experience declining mobility, pain and fatigue. The extent of motor fatigue and its impact on mobility and quality of life, in addition to other commonly reported impairments requires evaluation. Methods: An observational, case-control, cross-sectional design was used to assess 30 Polio survivors and 30 age- and sex-matched controls. Muscle strength and motor fatigue were assessed using fixed dynamometry. Fatigue, pain and quality of life were assessed using the Piper Fatigue Scale, the Fatigue Severity Scale, visual analogue scales and the RAND Short Form-36, respectively. An 8-min walking test, including physiological cost index (PCI), evaluated mobility. Results: A significant difference in motor fatigue was identified only in hand grip ( p = 0.03). Polio survivors were significantly weaker ( p < 0.001) and more fatigued ( p < 0.001) than controls. Motor fatigue was not related to subjective fatigue, mobility or quality of life. Muscle strength predicted mobility. Pain and fatigue were associated with lower mental quality of life, while PCI was associated with physical quality of life. Conclusion: Motor fatigue has been identified in Polio survivors but was only significantly different in hand grip, using this approach. Pain, fatigue and elevated energy cost of walking negatively influenced quality of life. Motor fatigue was unrelated to subjective fatigue, mobility or quality of life. [ABSTRACT FROM AUTHOR]

BACKGROUND: Factors determining the clinically isolated syndrome (CIS) patient's likelihood of developing multiple sclerosis (MS) are important for the clinician who needs to identify patients warranting immunomodulatory treatments. OBJECTIVE: To determine whether motor abnormalities found during the initial demyelinating event imply an increased risk of a second event within the first year. METHODS: Fifty-two early onset CIS patients, volunteered to participate in the prospective study. Motor parameters collected at onset included gait, balance, lower limb peak isometric strength and fatigue index parameters. At the end of one year, patients were subdivided into two groups, those who had experienced a second demyelinating attack suggestive of MS and those who maintained their clinical status. RESULTS: Forty-nine patients were included in the final analysis. Within the first year, 24 patients experienced a second attack, while 25 maintained their neurological status. Patients who suffered a second demyelinating attack, demonstrated reduced overall lower limb peak strength compared with patients who maintained their clinical status (411.9 (S.E. = 32.1) vs. 514.8 (S.E. = 34.1). No differences were observed between groups in gait and balance parameters. CONCLUSION: An initial demyelinating event characterized by reduced lower limb strength can possibly suggest an increased risk of an early second attack. [ABSTRACT FROM AUTHOR]

Abstract: Background: Different walking capacity test formats are applied, but their impact on the gait pattern in persons with MS (pwMS) has not yet been investigated according to baseline velocity performance. Objective: To assess, in pwMS with different ambulation dysfunction, the impact of speed instructions and previous walking tests (2 and 6min walking test; 2MWT and 6MWT) on spatiotemporal gait parameters. Methods: 27 participants, divided in three groups based on usual gait speed (Most Limited Community Walkers; MLCW<0.82m/s, CW>1.14m/s, LCW show intermediate values), completed the 2MWT and 6MWT. Before and after each test, they walked on the GAITRite walkway system at both usual and fastest speed. Spatio-temporal gait parameters were measured and analyzed with ANOVA. Results: All gait parameters in the MLCW were significantly different from other groups. In contrast to the MLCW, the LCW and CW subgroups showed greater velocity in the fastest compared to usual speed condition, associated with a significant increase in cadence and step length. After the 6MWT, small changes in cadence at usual speed and step time at fastest speed were observed in the MLCW subgroup only. No impact of the 2MWT on gait parameters was found in any group. Conclusions: The ability to accelerate was dependent on the severity of ambulatory dysfunction. Prolonged walking during the 6MWT has, in contrast to the 2MWT, some impact on gait parameters in the most disabled group only. [Copyright &y& Elsevier]

Objectives: Fatigue is a frequent and often disabling symptom in patients with post-COVID syndrome. To better understand and evaluate the symptom of motor fatigue in the context of the post-COVID syndrome, we conducted treadmill walking tests to detect the phenomenon of motor fatigability or to evaluate whether evidence of organic lesions of the motor system could be found, similar to patients with multiple sclerosis., Method: Twenty-nine non-hospitalized patients with post-COVID syndrome completed the Fatigue Scale for Motor and Cognitive Function (FSMC) questionnaire to determine the trait component of subjective fatigue before they were tested on a treadmill walking at a moderate speed for up to 60 min or until exhaustion. During the walking test oxygen uptake, ventilation and acceleration data of both feet were collected. To determine motor performance fatigability, the Fatigue Index Kliniken Schmieder (FKS) was calculated using the attractor method., Results: The average walking duration was 42.7 ± 18.6 min with 15 subjects stopping the walking test prematurely. The FSMC score revealed a severe cognitive (37.6 ± 8.2) and motor (37.1 ± 7.8) fatigue averaged over all subjects but only two subjects showed an FKS above the normal range (>4), representing performance fatigability. There was no significant correlation between subjective fatigue (FSMC) and FKS as well as walking time. Absolute values of oxygen uptake and ventilation were in the normal range reported in literature ( r = 0.9, p < 0.05), although eight subjects did not produce a steady-state behavior., Conclusion: Almost all patients with post-COVID syndrome and subjectively severe motor fatigue, did not show motor fatigability nor severe metabolic anomalies. This is argued against organic, permanent damage to the motor system, as is often seen in MS. Many of the patients were - to our and their own surprise - motorically more exertable than expected., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Weich, Dettmers, Saile, Schleicher, Vieten and Joebges.)

Objectives: To evaluate the frequency of motor impairments in patients with recently diagnosed clinically isolated syndrome (CIS) suggestive of MS. Methods: Following a neurological examination, patients with CIS were subdivided into two groups according to the number of functional systems involved at onset. Groups consisted of monosymptomatic (n=35, mean EDSS=1.3 ± 0.2) and polysymptomatic (n=17, mean EDSS=2.6 ± 0.1) patients. Motor assessment included peak isometric torque and fatigue index (FI) measured at the knee and ankle bilaterally and spatiotemporal parameters of gait and postural control. Lesion load and atrophy were measured on a 3.0T brain MRI using MSAnalyze computerized software. Twenty eight age- and gender-matched healthy subjects served as controls for motor assessment. Results: Polysymptomatic patients demonstrated reduced peak strength and FI, slower gait velocity, narrower base of support and increased sway rate compared to healthy subjects and mono-symptomatic patients. Furthermore, polysymptomatic and monosymptomatic patient median score in T2-weighted volume lesions (mm^{3}) was 4875 and 1628, respectively. Conclusions: Evidence of two subtypes of CIS was established in context with MRI findings and motor deficits. Differentiating between these groups can potentially improve management of MS patients at the initial stages of the disease process. [ABSTRACT FROM AUTHOR]

Fatigue symptoms are reported by a majority of patients with multiple sclerosis (MS). Reliable assessment, however, is a demanding issue as the symptoms are experienced subjectively and as objective assessment strategies are missing. The objective of this study was to develop and validate a new tool, the Fatigue Scale for Motor and Cognitive Functions (FSMC), for the assessment of MS-related cognitive and motor fatigue. A total of 309 MS patients and 147 healthy controls were included into the validation study. The FSMC was tested against several external criteria (e.g. cognition, motivation, personality and other fatigue scales). The item-analysis and validation procedure showed that the FSMC is highly sensitive and specific in detecting fatigued MS patients, that both subscales significantly differentiated between patients and controls (p<0.01), and that internal consistency (Cronbach's alpha α>0.91) as well as test-retest reliability (r>0.80) were high. Cut-off values were determined to classify patients as mildly, moderately or severely fatigued. In conclusion, the FSMC is a new scale that has undergone validation based on a large sample of patients and that provides differential quantification and graduation of cognitive and motor fatigue. [ABSTRACT FROM AUTHOR]

Objectives – Effects of endurance training in multiple sclerosis (MS) patients complaining of motor fatigue. Materials and methods – Thirty MS patients complaining of fatigue with low to moderate disabilities randomly allocated to the intervention (thrice weekly 45-min intervals of endurance exercise) or control treatment (three 45-min episodes of stretching, balance training and coordination), both as ‘add-on’ therapy for 3 weeks during inpatient rehabilitation. Results – Maximal walking distance before intervention averaged 1043 ± 568 and 1163 ± 750 m in the two groups. The intervention group increased its maximal walking distance by 650 ± 474 m. The control group extended its walking distance by 96 ± 70 m. Conclusions – The present data confirm a strong effect of endurance exercise on maximal walking distance. Remarkably, there were no parallel improvements on the Modified Fatigue Impact Scale, the Beck Depression Inventory and the Hamburg Quality of Life Questionnaire for MS. [ABSTRACT FROM AUTHOR]

Background Multiple sclerosis (MS) patients experience fatigue as a chronic symptom that decreases quality of life. Commonly, fatigue in MS patients is manifested as decreased motor function during or after physical activity and is associated with changes in brain metabolism. Objective To determine brain activation patterns in MS patients and healthy controls during a simple motor task before and after fatiguing hand-grip exercise. Methods Functional magnetic resonance imaging (fMRI) scans were conducted on 10 MS patients and 13 healthy controls during 4-finger flexion and extension in rested and fatigued states. Results Before the fatigue protocol, MS patients had greater activation in the contralateral primary motor cortex, insula, and cingulate gyrus than controls. Following fatiguing exercise, controls showed increased activation of precentral gyrus and insula while patients did not show any activation increases and actually decreased activity to the insula. Conclusion Results indicate that before fatiguing exercise, MS patients marshaled more brain activation compared to controls, which may represent functionally adaptive changes in response to demyelination. This increased activation may suggest that patients require more effort to perform even simple motor tasks, possibly because peripheral or central signals for fatigue are chronically enhanced. When fatigued further by muscle contraction, brain activation cannot be further increased. [ABSTRACT FROM AUTHOR]

Objective To assess the characteristics of the 6-min walk (6MW) in multiple sclerosis (MS) subjects of varied disability, and controls. To assess the correlation of 6MW to subjective measures of fatigue, health status and ambulation using the modified fatigue impact scale (MFIS), short form-36 Health Questionnaire physical component score and MS walking scale (MSWS). Methods Forty MS expanded disability status scale [(EDSS) 0–6.5] and 20 control subjects were recruited from a MS outpatient clinic. Subjects completed survey material and three 6MWs with 1-h interval rest in a single study visit. Results There was no practice effect or fatigability with repeat 6MW tests with a one-h rest period between test sessions. The 6MW had excellent intra-[intraclass correlation coefficient (ICC) = 0.95] and inter-rater (ICC = 0.91) reliability. MS subjects demonstrated reduced 6MW distance and speed compared with controls (P < 0.0001). Within the MS population 6MW distance was significantly reduced with increasing disability (P = 0.05). Compared with the EDSS, the 6MW had a stronger correlation to subjective measures of ambulation and physical fatigue: MSWS (r = -0.81 versus 0.69) and MFISphy (0.66 versus 0.63). Conclusions The 6MW is a feasible, reproducible, and reliable measure in MS. MS subjects demonstrate motor fatigue in both 6MW distance and speed compared with controls. In MS subjects there is an inverse relationship between motor fatigue and disability. 6MW has a strong correlation to subjective measures of ambulation and physical fatigue. [ABSTRACT FROM AUTHOR]

Motor fatigue is a common complaint of polio survivors and has a negative impact on activities of daily living. The aim of this study was to establish a normative database for hand grip strength and fatigue and to investigate differences between prior-polio subjects and normal controls. Static and dynamic hand grip fatigue and maximum voluntary isometric contraction (MVIC) of hand grip were measured in subjects with a prior history of polio (n = 44) and healthy controls (n = 494). A normative database of fatigue was developed using four indices of analysis. Compared with healthy controls, subjects with prior polio had significantly reduced hand grip strength but developed greater hand grip fatigue in only one fatigue index. Quantitative measurement of fatigue in the prior-polio population may be useful in order to detect change over time and to evaluate treatment strategies. [ABSTRACT FROM AUTHOR]

Abstract: The main purpose of this study was to investigate effects of motor fatigue on brain activation in humans, using fMRI. First, we assessed brain activation that correlated with muscle activity during brief contractions at different force levels (force modulation). Second, a similar analysis was done for sustained contractions inducing motor fatigue. Third, we studied changes in brain activation due to motor fatigue over time. And fourth, we investigated cross-over effects of fatigue by comparing brain activation before and after the fatiguing condition during simple and high-order motor tasks (reaction time tasks). Several motor areas in the brain showed increased activity with increased muscle activity, both during force modulation and motor fatigue. Interestingly, the cerebellum showed a smaller increase in activation, during compensatory activation due to fatigue, while additional activation was found in the pre-supplementary motor area and in a frontal area. During motor fatigue, there was a decrease in force production, an increase in force variability, and an increase in muscle activity. Brain areas comparable with the aforementioned areas also showed stronger activation over time. After fatigue, reaction time task performance remained the same (compared to before fatigue), while increased activation in orbitofrontal areas was found. Furthermore, there was a reduction in subjects'' maximal voluntary contraction force, accompanied by a decrease in activation of the supplementary motor area (SMA). These results suggest that especially the activity in the SMA and frontal areas is affected by motor fatigue. [Copyright &y& Elsevier]

Multiple Sclerosis (MS) is characterized by demyelination and neurodegeneration of the central nervous system and causes excessive fatigue in more than 80% of the patients. The pathophysiologic mechanisms causing fatigue are still largely unknown. In 46 right-handed patients with relapsing-remitting MS and 25 right-handed controls, we performed diffusion MRI and applied streamline based probabilistic tractography to derive unilateral anatomical connectivity maps for the white matter of the right and left hemispheres. The maps provide an indication how often a streamline has passed through a given voxel. Since tractography based anatomical connectivity mapping (ACM) is sensitive to disease-induced changes in anatomical connectivity, we used ACM to test whether motor fatigue is associated with altered ipsi-hemispherical anatomical connectivity in the major motor output pathway, the corticospinal tract (CST). Patients had higher mean ACM values in the CST than healthy controls. This indicated that a higher number of streamlines, starting from voxels in the same hemisphere, travelled through the CST and may reflect an accumulated disease-induced disintegration of CST. The motor subscale of the Fatigue Scale for Motor and Cognitive functions (FSMC MOTOR ) was used to define sub-groups with (n = 29, FSMC MOTOR score ≥ 27) and without motor fatigue (n = 17, FSMS MOTOR score ≤ 26). Patients without fatigue only showed higher ACM values in right CST, while mean ACM values were unaltered in left CST. The higher the mean ACM values in the left relative to the right CST, the more patients reported motor fatigue. Left-right asymmetry in anatomical connectivity outside the CST did not scale with individual motor fatigue. Our results link lateralized changes of tractography-based microstructural properties in the CST with motor fatigue in relapsing-remitting MS., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)