BACKGROUND: The individual experience of fatigue and fatigability in individuals with Multiple Sclerosis (MS) can vary greatly, beyond the high prevalence of fatigue in MS. Although fatigue is known as a common symptom that affects and potentially limits individuals with MS, it has recently been determined that fatigability also causes consequences that limit individuals\' daily lives. The purpose of this study was to compare the associations between self-reported levels of fatigue, measured fatigability, and estimates of functional capacity in people with MS and sex- and age-matched healthy individuals.
METHODS: Twenty-three individuals with Relapsing-Remitting MS (RRMS) diagnosis and 23 age- and sex-matched healthy individuals were included in the study. To examine the fatigability level Dynamic and Static Fatigue Index were used for gross and pinch-grip, and manual dexterity and functionality levels the Scale for the Assessment and Rating of Ataxia (SARA), Nine Hole Peg Test (NHPT), and Dexterity Questionnaire-24 (DextQ-24) were used. While the Fatigue Severity Scale (FSS) and Fatigue Impact Scale (FIS) were used to examine self-reported fatigue, the Beck Depression Inventory (BDI) was used to assess emotional status.
RESULTS: There was no difference between RRMS and healthy individuals in terms of fatigability levels (p > 0.05). While the relationship between Static and Dynamic Fatigue Index gross grip fatigability and FSS and FIS was not found to be statistically significant, the relationship between non-dominant side pinch grip Static Fatigue Index and FSS and FIS was significant. In addition, the relationship between the non-dominant side gross grip Static Fatigue Index and the DextQ-24 dressing and daily activities subsections, and the dominant side pinch grip Dynamic Fatigue Index and the television/compact disk/digital video disk subsection of DextQ-24 was significant (p < 0.05).
CONCLUSIONS: Fatigability was related to daily life upper limb use for gross grip and self-reported fatigue for pinch grip in individuals with RRMS. It was concluded that future studies focusing on hand fatigability could also consider manual dexterity and self-reported fatigue in individuals with MS from the early-stage. Clarifying the relationship of between fatigability and self-reported fatigue to functioning will allow clinicians to plan more appropriate and directed treatment approaches for individuals with RRMS.
BACKGROUND: ClinicalTrials.gov NCT05880745.

BACKGROUND: The present study aimed to investigate whether head and neck cooling (at 18 °C next to the skin) and fatiguing submaximal exercise at a thermoneutral ambient temperature can induce peripheral and central responses in healthy men and those with multiple sclerosis (MS).
METHODS: A local head-neck cooling (at 18 °C next to the skin) intervention in men with a relapsing-remitting form of MS (n = 18; age 30.9 ± 8.1 years) and healthy men (n = 22; age 26.7 ± 5.9 years) was assessed. Men in both groups performed 100 intermittent isometric knee extensions with 5 s contractions and 20 s of rest. The primary variables were measured before exercise, after 50 and 100 repetitions, and 1 h after recovery. The central activation ratio, maximal voluntary contraction, electrically induced force, electromyography, contractile properties, blood markers, muscle temperature, and perception of effort were measured.
RESULTS: Compared with noncooled conditions, head and neck cooling increased the central capacity to activate exercising muscles but resulted in greater exercise-induced peripheral fatigue in men with MS (p < 0.05). Local cooling did not affect motor accuracy or the amplitude of electromyography signals; however, these factors were related to the intensity of the motor task (p > 0.05). The changes in central and peripheral fatigability induced by local cooling during submaximal exercise were more pronounced in men with MS than in healthy men (p < 0.05).
CONCLUSIONS: Head and neck cooling enhances central activation of muscles during exercise, leading to improved exercise performance compared with noncooled conditions in men with MS.

BACKGROUND: Fatigue stands out as a prevalent and debilitating symptom in both Multiple Sclerosis (MS) and the aging population. Traditional methods for measuring perceived fatigue may not adequately account for individual activity differences, leading to varied prevalence rates. Perceived fatigability anchors fatigue to specific activities with predetermined intensity and duration, thereby mitigating self-pacing bias. Despite its potential, perceived fatigability is poorly understood in older adults, particularly those with neurological conditions, including MS. This study thus aimed to (1) investigate whether, among older adults, MS was associated with worse perceived physical and mental fatigability; (2) evaluate whether, among older adults with MS (OAMS), greater patient-reported disease-related disability was associated with worse perceived physical and mental fatigability.
METHODS: Participants were 96 older adults with a physician-confirmed diagnosis of MS (mean age: 64.6 ± 4.2) and 110 healthy controls (mean age: 68.2 ± 7.2), all confirmed to be dementia-free through established case conference procedures. Physical and mental fatigability were measured using the Pittsburgh Fatigability Scale, a 10-item questionnaire (score range: 0 to 50) designed to assess fatigue levels that individuals expect to feel after engaging in a range of typical activities for older adults. MS disease-related disability was assessed with the Patient Determined Disease Steps scale, which ranges from 0 (normal) to 8 (bedridden), with scores ≥ 2 indicating worse MS-related disability after a median split. Separate linear regression models were performed to investigate associations between group status (MS vs. Control) as the predictor and perceived physical and mental fatigability scores as the outcome variables. Within the MS group, additional linear regression models were performed to explore the relationship between disease-related disability and fatigability levels. All models adjusted for age, sex, race, education, global health, general cognitive function, and depressive symptoms levels.
RESULTS: The fully adjusted models yielded the following key findings: OAMS reported significantly higher levels of perceived physical fatigability (M = 25.11 ± 9.67) compared to controls (M = 17.95 ± 8.35) (p = 0.003). Similarly, the perceived mental fatigability in OAMS (M = 16.82 ± 11.79) was significantly greater than that in controls (M = 9.15 ± 7.12) (p = 0.003). Within the MS group, individuals with greater disease-related disability reported significantly greater levels of both physical (M = 30.13 ± 7.71 vs. 18.67 ± 8.00, p < 0.001) and mental fatigability (M = 20.31 ± 12.18 vs. 12.33 ± 9.69, p = 0.009) compared to those with lower MS-related disability. Of note, the significance of these findings persisted in models that adjusted for depressive symptoms.
CONCLUSIONS: Our study provides compelling evidence that OAMS exhibit significantly higher perceived physical and mental fatigability compared to healthy controls. Additionally, worse MS-related disability correlates with worse physical and mental fatigability. These results persist after adjusting for confounders including depressive symptoms. Our findings underscore the necessity of holistic management strategies that cater to both physical and psychological aspects of MS, laying a foundation for future studies to uncover the pathophysiological mechanisms of fatigability in older adults with and without MS.

Sex as a biological variable is an underappreciated aspect of biomedical research, with its importance emerging in more recent years. This review assesses the current understanding of sex differences in human physical performance. Males outperform females in many physical capacities because they are faster, stronger and more powerful, particularly after male puberty. This review highlights key sex differences in physiological and anatomical systems (generally conferred via sex steroids and puberty) that contribute to these sex differences in human physical performance. Specifically, we address the effects of the primary sex steroids that affect human physical development, discuss insight gained from an observational study of \'real-world data\' and elite athletes, and highlight the key physiological mechanisms that contribute to sex differences in several aspects of physical performance. Physiological mechanisms discussed include those for the varying magnitude of the sex differences in performance involving: (1) absolute muscular strength and power; (2) fatigability of limb muscles as a measure of relative performance; and (3) maximal aerobic power and endurance. The profound sex-based differences in human performance involving strength, power, speed and endurance, and that are largely attributable to the direct and indirect effects of sex-steroid hormones, sex chromosomes and epigenetics, provide a scientific rationale and framework for policy decisions on sex-based categories in sports during puberty and adulthood. Finally, we highlight the sex bias and problem in human performance research of insufficient studies and information on females across many areas of biology and physiology, creating knowledge gaps and opportunities for high-impact studies.

OBJECTIVE: Fatigue (subjective perception) and fatigability (objective motor performance worsening) are relevant aspects of disability in individuals with spinal muscular atrophy (SMA). The effect of nusinersen on fatigability in SMA patients has been investigated with conflicting results. We aimed to evaluate this in adult with SMA3.
METHODS: We conducted a multicenter retrospective cohort study, including adult ambulant patients with SMA3, data available on 6-minute walk test (6MWT) and Hammersmith Functional Motor Scale-Expanded (HFMSE) at baseline and at least at 6 months of treatment with nusinersen. We investigated fatigability, estimated as 10% or higher decrease in walked distance between the first and sixth minute of the 6MWT, at baseline and over the 14-month follow-up.
RESULTS: Forty-eight patients (56% females) were included. The 6MWT improved after 6, 10, and 14 months of treatment (p < 0.05). Of the 27 patients who completed the entire follow-up, 37% improved (6MWT distance increase ≥30 m), 48.2% remained stable, and 14.8% worsened (6MWT distance decline ≥30 m). Fatigability was found at baseline in 26/38 (68%) patients and confirmed at subsequent time points (p < 0.05) without any significant change over the treatment period. There was no correlation between fatigability and SMN2 copy number, sex, age at disease onset, age at baseline, nor with 6MWT total distance and baseline HFMSE score.
CONCLUSIONS: Fatigability was detected at baseline in approximately 2/3 of SMA3 walker patients, without any correlation with clinical features, included motor performance. No effect on fatigability was observed during the 14-month treatment period with nusinersen.

OBJECTIVE: Based on the critical power (Pc or critical force; Fc) concept, a recent mathematical model formalised the proportional link between the decrease in maximal capacities during fatiguing exercises and the amount of impulse accumulated above Fc. This study aimed to provide experimental support to this mathematical model of muscle fatigability in the severe domain through testing (i) the model identifiability using non-exhausting tests and (ii) the model ability to predict time to exhaustion (tlim) and maximal force (Fmax) decrease.
METHODS: The model was tested on eight participants using electrically stimulated adductor pollicis muscle force. The Fmax was recorded every 15 s for all tests, including five constant tests to estimate the initial maximal force (Fi), Fc, and a time constant (τ). The model\'s parameters were used to compare the predicted and observed tlim values of the incremental ramp test and Fmax(t) of the sine test.
RESULTS: The results showed that the model accurately estimated Fi, Fc, and τ (CI95% = 2.7%Fi and 9.1 s for Fc and τ, respectively; median adjusted r2 = 0.96) and predicted tlim and Fmax with low systematic and random errors (11 ± 20% and - 1.8 ± 7.7%Fi, respectively).
CONCLUSIONS: This study revealed the potential applications of a novel mathematical formalisation that encompasses previous research on the critical power concept. The results indicated that the model\'s parameters can be determined from non-exhaustive tests, as long as maximal capacities are regularly assessed. With these parameters, the evolution of maximal capacities (i.e. fatigability) at any point during a known exercise and the time to exhaustion can be accurately predicted.

Cerebral palsy (CP) is the most common childhood-onset disability. The evolution of gait according to severity is well known amongst children and thought to peak between 8 and 12 years of age among those walking without assistive devices. However, among adults, clinical experience as well as scientific studies report, through clinical assessments, questionnaires and interviews, increasing walking difficulties leading to an increased dependency of assistive devices in everyday ambulation. For many individuals with CP, this change will occur around 30-40 years, with the risk of losing mobility increasing with age. This narrative review aims to first provide objective evidence of motor function and gait decline in adults with CP when ageing, and then to offer mechanistic hypotheses to explain those alterations. Many studies have compared individuals with CP to the typically developing population, yet the evolution with ageing has largely been understudied. Comorbid diagnoses comprise one of the potential determinants of motor function and gait decline with ageing in people with CP, with the first manifestations happening at an early age and worsening with ageing. Similarly, ageing appears to cause alterations to the neuromuscular and cardiovascular systems at an earlier age than their typically developing (TD) peers. Future studies should, however, try to better understand how the physiological particularities of CP change with ageing that could pave the way for better strategies for maintaining function and quality of life in people with CP.

This study aimed to compare neuromuscular fatigability of the elbow flexors and extensors between athletes with amputation (AMP) and athletes with spinal cord injury (SCI) for maximum voluntary force (MVF) and rate of force development (RFD). We recruited 20 para-athletes among those participating at two training camps (2022) for Italian Paralympic veterans. Ten athletes with SCI (two with tetraplegia and eight with paraplegia) were compared to 10 athletes with amputation (above the knee, N = 3; below the knee, N = 6; forearm, N = 1). We quantified MVF, RFD at 50, 100, and 150 ms, and maximal RFD (RFDpeak) of elbow flexors and extensors before and after an incremental arm cranking to voluntary fatigue. We also measured the RFD scaling factor (RFD-SF), which is the linear relationship between peak force and peak RFD quantified in a series of ballistic contractions of submaximal amplitude. SCI showed lower levels of MVF and RFD in both muscle groups (all p values ≤ 0.045). Despite this, the decrease in MVF (Cohen\'s d = 0.425, p < 0.001) and RFDpeak (d = 0.424, p = 0.003) after the incremental test did not show any difference between pathological conditions. Overall, RFD at 50 ms showed the greatest decrease (d = 0.741, p < 0.001), RFD at 100 ms showed a small decrease (d = 0.382, p = 0.020), and RFD at 150 ms did not decrease (p = 0.272). The RFD-SF decreased more in SCI than AMP (p < 0.0001). Muscle fatigability impacted not only maximal force expressions but also the quickness of ballistic contractions of submaximal amplitude, particularly in SCI. This may affect various sports and daily living activities of wheelchair users. Early RFD (i.e., ≤50 ms) was notably affected by muscle fatigability.

OBJECTIVE: The performance metric associated with the execution of the 1-min sit-to-stand (1STS) typically relies on the number repetitions completed in 1 min. This parameter presents certain limitations (e.g., ceiling effect, motivational factors) which can impede its interpretation. Introducing additional parameters, such as neuromuscular fatigability level, could enhance the informative value of the 1STS and facilitate its interpretation. This study aimed to assess (i) whether the 1STS induces fatigability and (ii) the reliability of the fatigability level.
METHODS: Forty young, healthy, and active participants underwent the 1STS twice during the same session. Isolated sit-to-stand maneuvers were performed before, immediately, and 1 min after completing the 1STS. A mobile app was utilized to obtain time (STST), velocity (STSV), and muscle power (STSP) from these sit-to-stand maneuvers. The pre-post change in these parameters served as the fatigability marker. Reliability was assessed using the intra-class correlation coefficient (ICC) and the coefficient of variation (CV).
RESULTS: The mean number of repetitions during the 1STS was 63 ± 9. Significant decline in performance was observed for STST (13 ± 8%), STSV (-11.2 ± 6%), and STSP (-5.2 ± 3%), with more than 74% of participants exhibiting a decline beyond the minimal detectable change. Excellent between-session reliability (ICC ≥ 0.9; CV ≤ 5.3) was observed for the mobile app variables.
CONCLUSIONS: The 1STS induces significant levels of fatigability. The fatigability indicators derived from the mobile app demonstrated remarkable reliability. Utilizing this user-friendly interface for computing fatigability may empower professionals to acquire insightful complementary indicators from the 1STS.

Long-term hepatic damage is associated with human morbidity and mortality owing to numerous pathogenic factors. A variety of studies have focused on improving liver health using natural products and herbal medicines. We aimed to investigate the effect of enzyme-treated Zizania latifolia ethanol extract (ETZL), which increases the content of tricin via enzymatic hydrolysis, for 8 weeks on liver-related outcomes, lipid metabolism, antioxidant activity, and fatigue compared to a placebo. Healthy Korean adult males aged 19-60 years were randomized into ETZL treatment and placebo groups, and alcohol consumption was 24.96 and 28.64 units/week, respectively. Alanine transaminase, a blood marker associated with liver cell injury, significantly decreased after 8 weeks compared to the baseline in the ETZL treatment group (p = 0.004). After 8 weeks, the treatment group showed significant changes in the levels of high-density lipoprotein and hepatic steatosis index compared to the baseline (p = 0.028 and p = 0.004, respectively). ETZL treatment tended to reduce antioxidant-activity-related factors, total antioxidant status, and malondialdehyde, but there was no significant difference. In the multidimensional fatigue scale, ETZL treatment showed a significant reduction in general fatigue and total-fatigue-related values after 8 weeks compared to the baseline (p = 0.012 and p = 0.032, respectively). Taken together, the 8-week treatment of enzyme-treated Zizania latifolia ethanol extract demonstrated positive effects on liver-related outcomes, lipid metabolism, and mental fatigue without adverse effects on safety-related parameters.