The MoxFo initiative-Mechanisms of action: Biomarkers in multiple sclerosis exercise studies.

BACKGROUND: As exercise exerts neurobiological and immunomodulatory effects, it might also act as a disease-modifying intervention in MS. However, a clear mechanistic link between exercise and disease-modifying effects in MS has yet to be established. OBJECTIVE: Establish recommendations for future mechanistic exercise studies in MS. METHODS: In regular meetings, members of the mechanisms of action group within the MoXFo (Moving eXercise research Forward in MS) initiative evaluated gaps of knowledge and discussed unmet needs in mechanistic MS research. RESULTS: We concluded that biomarkers assessed in translational studies in humans and animals are essential to decipher the underlying mechanisms of exercise in MS. Consequently, we defined clear definitions of different types of biomarkers examined in MS exercise studies and operationalized their use to align with the research question and optimal testing time points. Furthermore, we provide key considerations to improve the rigor of translational studies and defined minimal reporting criteria for animal studies. CONCLUSION: The resulting recommendations are intended to improve the quality of future mechanistic exercise studies in MS and consequently lead to a better understanding of therapeutic approaches.

Machine learning classification of multiple sclerosis patients based on raw data from an instrumented walkway.

BACKGROUND: Using embedded sensors, instrumented walkways provide clinicians with important information regarding gait disturbances. However, because raw data are summarized into standard gait variables, there may be some salient features and patterns that are ignored. Multiple sclerosis (MS) is an inflammatory neurodegenerative disease which predominantly impacts young to middle-aged adults. People with MS may experience varying degrees of gait impairments, making it a reasonable model to test contemporary machine leaning algorithms. In this study, we employ machine learning techniques applied to raw walkway data to discern MS patients from healthy controls. We achieve this goal by constructing a range of new features which supplement standard parameters to improve machine learning model performance. RESULTS: Eleven variables from the standard gait feature set achieved the highest accuracy of 81%, precision of 95%, recall of 81%, and F1-score of 87%, using support vector machine (SVM). The inclusion of the novel features (toe direction, hull area, base of support area, foot length, foot width and foot area) increased classification accuracy by 7%, recall by 9%, and F1-score by 6%. CONCLUSIONS: The use of an instrumented walkway can generate rich data that is generally unseen by clinicians and researchers. Machine learning applied to standard gait variables can discern MS patients from healthy controls with excellent accuracy. Noteworthy, classifications are made stronger by including novel gait features (toe direction, hull area, base of support area, foot length and foot area).

Prioritizing progressive MS rehabilitation research: A call from the International Progressive MS Alliance.

BACKGROUND: People with multiple sclerosis (MS) experience myriad symptoms that negatively affect their quality of life. Despite significant progress in rehabilitation strategies for people living with relapsing-remitting MS (RRMS), the development of similar strategies for people with progressive MS has received little attention. OBJECTIVE: To highlight key symptoms of importance to people with progressive MS and stimulate the design and implementation of high-quality studies focused on symptom management and rehabilitation. METHODS: A group of international research experts, representatives from industry, and people affected by progressive MS was convened by the International Progressive MS Alliance to devise research priorities for addressing symptoms in progressive MS. RESULTS: Based on information from the MS community, we outline a rationale for highlighting four symptoms of particular interest: fatigue, mobility and upper extremity impairment, pain, and cognitive impairment. Factors such as depression, resilience, comorbidities, and psychosocial support are described, as they affect treatment efficacy. CONCLUSIONS: This coordinated call to action-to the research community to prioritize investigation of effective symptom management strategies, and to funders to support them-is an important step in addressing gaps in rehabilitation research for people affected by progressive MS.

Moving exercise research in multiple sclerosis forward (the MoXFo initiative): Developing consensus statements for research.

Exercise as a subset of physical activity is a cornerstone in the management of multiple sclerosis (MS) based on its pleotropic effects. There is an exponential increase in the quantity of research on exercise in MS, yet a number of barriers associated with study content and quality hamper rapid progress in the field. To address these barriers and accelerate discovery, a new international partnership of MS-related experts in exercise has emerged with the goal of advancing the research agenda. As a first step, the expert panel met in May 2018 and identified the most urgent areas for moving the field forward, and discussed the framework for such a process. This led to identification of five themes, namely "Definitions and terminology," "Study methodology," "Reporting and outcomes," "Adherence to exercise," and "Mechanisms of action." Based on the identified themes, five expert groups have been formed, that will further (a) outline the challenges per theme and (b) provide recommendations for moving forward. We aim to involve and collaborate with people with MS/MS organizations (e.g. Multiple Sclerosis International Federation (MSIF) and European Multiple Sclerosis Platform (EMSP)) in all of these five themes. The generation of this thematic framework with multi-expert perspectives can bolster the quality and scope of exercise studies in MS that may ultimately improve the daily lives of people with MS.

Vigorous cool room treadmill training to improve walking ability in people with multiple sclerosis who use ambulatory assistive devices: a feasibility study.

BACKGROUND: Aerobic training has the potential to restore function, stimulate brain repair, and reduce inflammation in people with Multiple Sclerosis (MS). However, disability, fatigue, and heat sensitivity are major barriers to exercise for people with MS. We aimed to determine the feasibility of conducting vigorous harness-supported treadmill training in a room cooled to 16 °C (10 weeks; 3times/week) and examine the longer-term effects on markers of function, brain repair, and inflammation among those using ambulatory aids. METHODS: Ten participants (9 females) aged 29 to 74 years with an Expanded Disability Status Scale ranging from 6 to 7 underwent training (40 to 65% heart rate reserve) starting at 80% self-selected walking speed. Feasibility of conducting vigorous training was assessed using a checklist, which included attendance rates, number of missed appointments, reasons for not attending, adverse events, safety hazards during training, reasons for dropout, tolerance to training load, subjective reporting of symptom worsening during and after exercise, and physiological responses to exercise. Functional outcomes were assessed before, after, and 3 months after training. Walking ability was measured using Timed 25 Foot Walk test and on an instrumented walkway at both fast and self-selected speeds. Fatigue was measured using fatigue/energy/vitality sub-scale of 36-Item Short-Form (SF-36) Health Survey, Fatigue Severity Scale, modified Fatigue Impact Scale. Aerobic fitness (maximal oxygen consumption) was measured using maximal graded exercise test (GXT). Quality-of-life was measured using SF-36 Health Survey. Serum levels of neurotrophin (brain-derived neurotrophic factor) and cytokine (interleukin-6) were assessed before and after GXT. RESULTS: Eight of the ten participants completed training (attendance rates ≥ 80%). No adverse events were observed. Fast walking speed (cm/s), gait quality (double-support (%)) while walking at self-selected speed, fatigue (modified Fatigue Impact Scale), fitness (maximal workload achieved during GXT), and quality-of-life (physical functioning sub-scale of SF-36) improved significantly after training, and improvements were sustained after 3-months. Improvements in fitness (maximal respiratory exchange ratio and maximal oxygen consumption during GXT) were associated with increased brain-derived neurotrophic factor and decreased interleukin-6. CONCLUSION: Vigorous cool room training is feasible and can potentially improve walking, fatigue, fitness, and quality-of-life among people with moderate to severe MS-related disability. TRIAL REGISTRATION: The study was approved by the Newfoundland and Labrador Health Research Ethics Board (reference number: 2018.088) on 11/07/2018 prior to the enrollment of first participant (retrospectively registered at ClinicalTrials.gov: NCT04066972. Registered on 26 August 2019.

Exercise-Induced Brain Excitability Changes in Progressive Multiple Sclerosis: A Pilot Study.

BACKGROUND AND PURPOSE: Even a single bout of aerobic exercise (AE) enhances corticospinal excitability (CSE), a biomarker of neuroplasticity. Because neurodegeneration limits capacity for neuroplasticity, it is not clear whether AE would induce CSE changes in people with progressive multiple sclerosis (MS). METHODS: People with progressive MS (n = 10) requiring ambulatory assistive devices completed a graded maximal exercise test. Dual-energy x-ray absorptiometry was used to quantify body fat and lean mass. Before and following one 40-minute AE session using body weight-supported (<10% support) treadmill at moderate intensity, CSE was measured using transcranial magnetic stimulation. Variables included resting and active motor thresholds, motor evoked potential (MEP) amplitudes, recruitment curves, and length of the cortical silent period (CSP). RESULTS: Aerobic exercise reduced inhibition (shorter CSP) and increased excitation (increased MEP amplitude) only in the hemisphere corresponding to the stronger hand. Controlling for age, higher fitness and lower body fat significantly predicted exercise-induced reduction in resting motor threshold (ΔR = +0.458, P = 0.046) and CSP (ΔR = +0.568, P = 0.030), respectively. DISCUSSION AND CONCLUSIONS: Despite high levels of disability, capacity for exercise-induced neuroplasticity was retained among people with progressive MS. The hemisphere contralateral to the weaker hand was resistant to exercise-induced CSE changes, suggesting less neuroplastic potential. Lower fitness and higher body fat were associated with diminished exercise-induced CSE benefits, suggesting that therapists should consider interventions aimed at improving fitness and combating sedentarism to ultimately enhance the benefits of exercise on the brain.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A302).

miR-223 promotes regenerative myeloid cell phenotype and function in the demyelinated central nervous system.

In the injured central nervous system, myeloid cells, including macrophages and microglia, are key contributors to both myelin injury and repair. This immense plasticity emphasizes the need to further understand the precise molecular mechanisms that contribute to the dynamic regulation of myeloid cell polarization and function. Herein, we demonstrate that miR-223 is upregulated in multiple sclerosis (MS) patient monocytes and the alternatively-activated and tissue-regenerating M2-polarized human macrophages and microglia. Using miR-223 knock-out mice, we observed that miR-223 is dispensable for maximal pro-inflammatory responses, but is required for efficient M2-associated phenotype and function, including phagocytosis. Using the lysolecithin animal model, we further demonstrate that miR-223 is required to efficiently clear myelin debris and promote remyelination. These results suggest miR-223 constrains neuroinflammation while also promoting repair, a finding of important pathophysiological relevance to MS as well as other neurodegenerative diseases.

Oxygen Cost During Mobility Tasks and Its Relationship to Fatigue in Progressive Multiple Sclerosis.

OBJECTIVE: To compare the oxygen costs of mobility tasks between individuals with progressive multiple sclerosis (MS) using walking aids and matched controls and to determine whether oxygen cost predicted fatigue. DESIGN: Cross-sectional descriptive. SETTING: A rehabilitation research laboratory. PARTICIPANTS: A total of 14 adults with progressive MS (mean age ± SD [y], 54.07±8.46) using walking aids and 8 age- and sex-matched controls without MS (N=22). INTERVENTIONS: Participants performed 5 mobility tasks (rolling in bed, lying to sitting, sitting to standing, walking, climbing steps) wearing a portable metabolic cart. MAIN OUTCOME MEASURES: Oxygen consumption (V˙o2) during mobility tasks, maximal V˙o2 during graded maximal exercise test, perceived exertion, and task-induced fatigue were measured on a visual analog scale before and after mobility tasks. RESULTS: People with progressive MS had significantly higher oxygen cost in all tasks compared to controls (P<.05): climbing steps (3.60 times more in MS), rolling in bed (3.53), walking (3.10), lying to sitting (2.50), and sitting to standing (1.82). There was a strong, positive correlation between task-induced fatigue and oxygen cost of walking, (ρ [13]=0.626, P=.022). CONCLUSIONS: People with progressive MS used 2.81 times more energy on average for mobility tasks compared to controls. People with progressive MS experienced accumulation of oxygen cost, fatigue, and exertion when repeating tasks and higher oxygen cost during walking was related to greater perception of fatigue. Our findings suggest that rehabilitation interventions that increase endurance during functional tasks could help reduce fatigue in people with progressive MS who use walking aids.

Transcranial Magnetic Stimulation as a Potential Biomarker in Multiple Sclerosis: A Systematic Review with Recommendations for Future Research.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system. Disease progression is variable and unpredictable, warranting the development of biomarkers of disease status. Transcranial magnetic stimulation (TMS) is a noninvasive method used to study the human motor system, which has shown potential in MS research. However, few reviews have summarized the use of TMS combined with clinical measures of MS and no work has comprehensively assessed study quality. This review explored the viability of TMS as a biomarker in studies of MS examining disease severity, cognitive impairment, motor impairment, or fatigue. Methodological quality and risk of bias were evaluated in studies meeting selection criteria. After screening 1603 records, 30 were included for review. All studies showed high risk of bias, attributed largely to issues surrounding sample size justification, experimenter blinding, and failure to account for key potential confounding variables. Central motor conduction time and motor-evoked potentials were the most commonly used TMS techniques and showed relationships with disease severity, motor impairment, and fatigue. Short-latency afferent inhibition was the only outcome related to cognitive impairment. Although there is insufficient evidence for TMS in clinical assessments of MS, this review serves as a template to inform future research.

Factors Associated with Poor Sleep in Older Adults with Multiple Sclerosis.

PURPOSE: Canada has the highest rate of multiple sclerosis (MS) in the world. Sleep disturbance in individuals with MS is approximately four times higher than in the general population. This is concerning given that poor sleep quality negatively affects one's mental and physical well-being. The objectives of this study are (1) to document the prevalence of sleep problems in a Canadian sample of older individuals living with MS, (2) to identify demographic and clinical factors associated with poor sleep, and (3) to investigate the potential impact of possible sleep-promoting and sleep-interfering medications. METHOD: This study is a secondary analysis of sleep and related variables from the Canadian survey of health, lifestyle, and aging with multiple sclerosis study. The survey consists of 743 Canadians 55 years or older with a diagnosis of MS. We asked participants, "In the past 2 weeks, how much have you been bothered by problems sleeping?" RESULTS: Overall, 43% of patients with MS reported problems sleeping. The strongest associations were found between poor sleep and number of comorbidities, clinically significant anxiety, and a greater perceived impact of physical symptoms of MS on functioning. CONCLUSION: Sleep problems are prevalent in individuals with MS. Individuals who had clinically significant levels of anxiety were roughly two times more likely to have trouble sleeping when compared to individuals without anxiety. Efforts should focus on early identification and effective interventions for poor sleep in individuals living with MS.

Four birds with one stone? Reparative, neuroplastic, cardiorespiratory, and metabolic benefits of aerobic exercise poststroke.

PURPOSE OF REVIEW: Converging evidence from animal models of stroke and clinical trials suggests that aerobic exercise has effects across multiple targets. RECENT FINDINGS: The subacute phase is characterized by a period of heightened neuroplasticity when aerobic exercise has the potential to optimize recovery. In animals, low intensity aerobic exercise shrinks lesion size and reduces cell death and inflammation, beginning 24 h poststroke. Also in animals, aerobic exercise upregulates brain-derived neurotrophic factor near the lesion and improves learning. In terms of neuroplastic effects, clinical trial results are less convincing and have only examined effects in chronic stroke. Stroke patients demonstrate cardiorespiratory fitness levels below the threshold required to carry out daily activities. This may contribute to a 'neurorehabilitation ceiling' that limits capacity to practice at a high enough frequency and intensity to promote recovery. Aerobic exercise when delivered 2-5 days per week at moderate to high intensity beginning as early as 5 days poststroke improves cardiorespiratory fitness, dyslipidemia, and glucose tolerance. SUMMARY: Based on the evidence discussed and applying principles of periodization commonly used to prepare athletes for competition, we have created a model of aerobic training in subacute stroke in which training is delivered in density blocks (duration × intensity) matched to recovery phases.

Defining Optimal Aerobic Exercise Parameters to Affect Complex Motor and Cognitive Outcomes after Stroke: A Systematic Review and Synthesis.

Although poststroke aerobic exercise (AE) increases markers of neuroplasticity and protects perilesional tissue, the degree to which it enhances complex motor or cognitive outcomes is unknown. Previous research suggests that timing and dosage of exercise may be important. We synthesized data from clinical and animal studies in order to determine optimal AE training parameters and recovery outcomes for future research. Using predefined criteria, we included clinical trials of stroke of any type or duration and animal studies employing any established models of stroke. Of the 5,259 titles returned, 52 articles met our criteria, measuring the effects of AE on balance, lower extremity coordination, upper limb motor skills, learning, processing speed, memory, and executive function. We found that early-initiated low-to-moderate intensity AE improved locomotor coordination in rodents. In clinical trials, AE improved balance and lower limb coordination irrespective of intervention modality or parameter. In contrast, fine upper limb recovery was relatively resistant to AE. In terms of cognitive outcomes, poststroke AE in animals improved memory and learning, except when training was too intense. However, in clinical trials, combined training protocols more consistently improved cognition. We noted a paucity of studies examining the benefits of AE on recovery beyond cessation of the intervention.

Over-the-counter anti-oxidant therapies for use in multiple sclerosis: A systematic review.

BACKGROUND: Anti-oxidant compounds that are found in over-the-counter (OTC) supplements and foods are gaining interest as treatments for multiple sclerosis (MS). They are widely used by patients, sometimes without a clear evidence base. OBJECTIVE: We conducted a systematic review of animal and clinical research to determine the evidence for the benefits of OTC anti-oxidants in MS. METHODS: Using predefined criteria, we searched key databases. Two authors scrutinized all studies against inclusion/exclusion criteria, assessed study risk-of-bias and extracted results. RESULTS: Of the 3507 titles, 145 met criteria and included compounds, α(alpha)-lipoic acid (ALA), anti-oxidant vitamins, Ginkgo biloba, quercetin, resveratrol and epigallocatechin-3-gallate (ECGC). The strongest evidence to support OTC anti-oxidants was for compounds EGCG and ALA in animal models; both consistently showed anti-inflammatory/anti-oxidant effects and reduced neurological impairment. Only vitamin E, Ginkgo biloba and ALA were examined for efficacy in pilot clinical trials with either conflicting evidence or evidence of no benefit. CONCLUSION: OTC anti-oxidants EGCG and ALA show the most consistent benefit, however only in preclinical studies. There is no evidence that they alter MS relapses or progression. Future work should focus on testing more of these therapies for clinical efficacy before recommending them to MS patients.

Predictors of chronic cerebrospinal venous insufficiency procedure use among older people with multiple sclerosis: a national case-control study.

BACKGROUND: Following the initial reports of Chronic Cerebrospinal Venous Insufficiency (CCSVI) and the purported curative potential of venoplasty, (coined the 'liberation' procedure) Canadians living with multiple sclerosis (MS) began to travel abroad to receive the unregulated procedure, often placing them at odds with their health providers. The purpose of this study was to determine the factors influencing older MS patients' decision to undergo the procedure in order to develop more specific and targeted health information. METHODS: We performed secondary analysis of data collected as part of the 'Canadian Survey of Health Lifestyle and Aging with MS' from people over the age of 55 years with MS symptoms for 20 or more years. The survey consisted of self-reported information on impairments, disability, participation, demographics, personal and environmental factors. In order to compare respondents who underwent the procedure to those who did not and to develop a predictive model, we created a comparison group using a case-control algorithm, controlling for age, gender and education, and matching procedure cases to controls 1:3. We used multivariate stepwise least likelihood regression of 'a priori' variables to determine predictive factors. RESULTS: The prevalence of the 'liberation' procedure in our sample was 12.8% (95/743), substantially lower than reported in previous studies of complementary/alternative treatments in MS. The predictive model contained five factors; living alone (Odds ratio 0.24, 95%CI 0.09-0.63), diagnosis of anxiety (Odds ratio 0.29, 95%CI 0.10 - 0.84), rating of neurologist's helpfulness (Odds ratio 0.56, 95%CI 0.44 -0 .71), Body Mass Index (Odds ratio 0.93, 95%CI, 0.89 - 0.98) and perceived physical impact of MS (Odds ratio 1.02, 95%CI 1.01 - 1.04). CONCLUSIONS: Predictive factors differed from previous studies of complementary/alternative treatment use likely due to both the invasiveness of the procedure and the advanced age of our study cohort. Our findings suggest that health professionals should target information on the risks and benefits of unregulated procedures to those patients who feel dissatisfied with their neurologist and they should include family members in discussions since they may be providing the logistical support to travel abroad and undergo the 'liberation' procedure. Our findings may be applicable to others with chronic disabling conditions who contemplate the user-pay unregulated invasive procedures available to them.

Determining the activation of gluteus medius and the validity of the single leg stance test in chronic, nonspecific low back pain.

OBJECTIVES: To determine the activation of the gluteus medius in persons with chronic, nonspecific low back pain compared with that in control subjects, and to determine the association of the clinical rating of the single leg stance (SLS) with chronic low back pain (CLBP) and gluteus medius weakness. DESIGN: Cohort-control comparison. SETTING: Academic research laboratory. PARTICIPANTS: Convenience sample of people (n=21) with CLBP (>12wk) recruited by local physiotherapists, and age- and sex-matched controls (n=22). Subjects who received specific pain diagnoses were excluded. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Back pain using the visual analog scale (mm); back-related disability using the Oswestry Back Disability Index (%); strength of gluteus medius measured using a hand dynamometer (N/kg); SLS test; gluteus medius onset and activation using electromyography during unipedal stance on a forceplate. RESULTS: Individuals in the CLBP group exhibited significant weakness in the gluteus medius compared with controls (right, P=.04; left, P=.002). They also had more pain (CLBP: mean, 20.50mm; 95% confidence interval [CI], 13.11-27.9mm; control subjects: mean, 1.77mm; 95% CI, -.21 to 3.75mm) and back-related disability (CLBP: mean, 18.52%; 95% CI, 14.46%-22.59%; control subjects: mean, .68%; 95% CI, -.41% to 1.77%), and reported being less physically active. Weakness was accompanied by increased gluteus medius activation during unipedal stance (R=.50, P=.001) but by no difference in muscle onset times. Although greater gluteus medius weakness was associated with greater pain and disability, there was no difference in muscle strength between those scoring positive and negative on the SLS test (right: F=.002, P=.96; left: F=.1.75, P=.19). CONCLUSIONS: Individuals with CLBP had weaker gluteus medius muscles than control subjects without back pain. Even though there was no significant difference in onset time of the gluteus medius when moving to unipedal stance between the groups, the CLBP group had greater gluteus medius activation. A key finding was that a positive SLS test did not distinguish the CLBP group from the control group, nor was it a sign of gluteus medius weakness.

Incongruence between Cardiorespiratory Fitness and Subjective Reports of Physical Activity in Multiple Sclerosis: A Focus on Sex Differences.

Purpose: The link between moderate- to vigorous-intensity physical activity (MVPA) and cardiorespiratory fitness in individuals with multiple sclerosis (MS) remains unclear. This study examined the relationship between self-reported MVPA and objectively assessed cardiorespiratory fitness, emphasizing sex differences. Methods: 107 adults with MS (77 females), aged (mean ± standard deviation) 47.2 ± 10.2 years, were recruited from a local MS clinic. Fitness was measured as maximal oxygen uptake (V̇O2max) during a graded maximal exercise test using a recumbent stepper. MVPA (24-hour recall) was estimated as the duration of activities ≥ 3 MET (metabolic equivalent of task). MET-minutes were calculated by multiplying MET by duration. We explored sex differences in self-reported MVPA, cardiorespiratory fitness, and disability; examined sex differences in associations between these variables; and investigated whether MET-minutes of MVPA predicted V̇O2max in females and males. Results: Mean V̇O2max was 24.79 mL·kg-1·min-1, indicating poor cardiorespiratory fitness levels, despite high levels of self-reported MVPA (mean = 412.5 MET-minutes). Fifty-three percent of males and 40% of females had V̇O2max levels below the 20th age- and sex-standardized population percentile, indicating poor cardiorespiratory fitness. There were statistically significant associations between MVPA and V̇O2max (Rho = 0.27, p = .01), as well as disability and V̇O2max (Rho = -0.35, p = .02), in females but not males. A regression model using sex, age, body mass, disability, and MVPA to estimate V̇O2max was valid in predicting V̇O2max values that were statistically equivalent to those measured in the laboratory in females but not males. However, the inclusion of MVPA did not add to the predictive value of this equation. Conclusions: Despite reporting high levels of MVPA, people with MS had poor cardiorespiratory fitness. MVPA, fitness, and disability were associated in females only, indicating that sex differences should be considered in fitness appraisal. Self-reported MVPA did not predict fitness, suggesting 24-hour recall may not be representative of true activity or fitness levels in persons with MS. Future work should examine sex differences in associations between MVPA and fitness using objective measures such as accelerometry.

Weak grip strength among persons with multiple sclerosis having minimal disability is not related to agility or integrity of the corticospinal tract.

INTRODUCTION: Mobility impairment is common in multiple sclerosis (MS); however, agility has received less attention. Agility requires strength and neuromuscular coordination to elicit controlled propulsive rapid whole-body movement. Grip strength is a common method to assess whole body force production, but also reflects neuromuscular integrity and global brain health. Impaired agility may be linked to loss of neuromuscular integrity (reflected by grip strength or corticospinal excitability). OBJECTIVES: We aimed to determine whether grip strength would be associated with agility and transcranial magnetic stimulation (TMS)-based indices of corticospinal excitability and inhibition in persons with MS having low disability. We hypothesized that low grip strength would predict impaired agility and reflect low corticospinal excitability. METHODS: We recruited 34 persons with relapsing MS (27 females; median [range] age 45.5 [21.0-65.0] years) and mild disability (median [range] Expanded Disability Status Scale 2.0 [0-3.0]), as well as a convenience sample of age- and sex-matched apparently healthy controls. Agility was tested by measuring hop length during bipedal hopping on an instrumented walkway. Grip strength was measured using a calibrated dynamometer. Corticospinal excitability and inhibition were examined using TMS-based motor evoked potential (MEP) and corticospinal silent period (CSP) recruitment curves, respectively. RESULTS: MS participants had significantly lower grip strength than controls independent of sex. Females with and without MS had weaker grip strength than males. There were no statistically significant sex or group differences in agility. After controlling for sex, weaker grip strength was associated with shorter hop length in controls only (r = 0.645, p < .05). Grip strength did not significantly predict agility in persons with MS, nor was grip strength predicted by corticospinal excitability or inhibition. CONCLUSIONS: In persons with MS having low disability, grip strength (normalized to body mass) was reduced despite having intact agility and walking performance. Grip strength was not associated with corticospinal excitability or inhibition, suggesting peripheral neuromuscular function, low physical activity or fitness, or other psychosocial factors may be related to weakness. Low grip strength is a putative indicator of early neuromuscular aging in persons with MS having mild disability and normal mobility.

Transcranial magnetic stimulation enhances the specificity of multiple sclerosis diagnostic criteria: a critical narrative review.

Background: Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease that involves attacks of inflammatory demyelination and axonal damage, with variable but continuous disability accumulation. Transcranial magnetic stimulation (TMS) is a noninvasive method to characterize conduction loss and axonal damage in the corticospinal tract. TMS as a technique provides indices of corticospinal tract function that may serve as putative MS biomarkers. To date, no reviews have directly addressed the diagnostic performance of TMS in MS. The authors aimed to conduct a critical narrative review on the diagnostic performance of TMS in MS. Methods: The authors searched the Embase, PubMed, Scopus, and Web of Science databases for studies that reported the sensitivity and/or specificity of any reported TMS technique compared to established clinical MS diagnostic criteria. Studies were summarized and critically appraised for their quality and validity. Results: Seventeen of 1,073 records were included for data extraction and critical appraisal. Markers of demyelination and axonal damage-most notably, central motor conduction time (CMCT)-were specific, but not sensitive, for MS. Thirteen (76%), two (12%), and two (12%) studies exhibited high, unclear, and low risk of bias, respectively. No study demonstrated validity for TMS techniques as diagnostic biomarkers in MS. Conclusions: CMCT has the potential to: (1) enhance the specificity of clinical MS diagnostic criteria by "ruling in" true-positives, or (2) revise a diagnosis from relapsing to progressive forms of MS. However, there is presently insufficient high-quality evidence to recommend any TMS technique in the diagnostic algorithm for MS.

Disrupted hemodynamic response within dorsolateral prefrontal cortex during cognitive tasks among people with multiple sclerosis-related fatigue.

INTRODUCTION: Mental fatigue is an early and enduring symptom in persons with autoimmune disease particularly multiple sclerosis (MS). Neuromodulation has emerged as a potential treatment although optimal cortical targets have yet to be determined. We aimed to examine cortical hemodynamic responses within bilateral dorsolateral prefrontal cortex (dlPFC) and frontopolar areas during single and dual cognitive tasks in persons with MS-related fatigue compared to matched controls. METHODS: We recruited persons (15 MS and 12 age- and sex-matched controls) who did not have physical or cognitive impairment and were free from depressive symptoms. Functional near infrared spectroscopy (fNIRS) registered hemodynamic responses during the tasks. We calculated oxyhemoglobin peak, time-to-peak, coherence between channels (a potential marker of neurovascular coupling) and functional connectivity (z-score). RESULTS: In MS, dlPFC demonstrated disrupted hemodynamic coherence during both single and dual tasks, as evidenced by non-significant and negative correlations between fNIRS channels. In MS, reduced coherence occurred in left dorsolateral PFC during the single task but occurred bilaterally as the task became more challenging. Functional connectivity was lower during dual compared to single tasks in the right dorsolateral PFC in both groups. Lower z-score was related to greater feelings of fatigue. Peak and time-to-peak hemodynamic response did not differ between groups or tasks. CONCLUSIONS: Hemodynamic responses were inconsistent and disrupted in people with MS experiencing mental fatigue, which worsened as the task became more challenging. Our findings point to dlPFC, but not frontopolar areas, as a potential target for neuromodulation to treat cognitive fatigue.