Lowered ratio of corticospinal excitation to inhibition predicts greater disability, poorer motor and cognitive function in multiple sclerosis.

Objective: Investigate excitatory-inhibitory (E/I) (im)balance using transcranial magnetic stimulation (TMS) in individuals with Multiple Sclerosis (MS) and determine its validity as a neurophysiological biomarker of disability. Methods: Participants with MS (n = 83) underwent TMS, cognitive, and motor function assessments. TMS-induced motor evoked potential amplitudes (excitability) and cortical silent periods (inhibition) were assessed bilaterally through recruitment curves. The E/I ratio was calculated as the ratio of excitation to inhibition. Results: Participants with greater disability (Expanded Disability Status Scale, EDSS≥3) exhibited lower excitability and increased inhibition compared to those with lower disability (EDSS<3). This resulted in lower E/I ratios in the higher disability group. Individuals with higher disability presented with asymmetrical E/I ratios between brain hemispheres, a pattern not present in the group with lower disability. In regression analyses controlling for demographics, lowered TMS-probed E/I ratio predicted variance in disability (R2 = 0.37, p < 0.001), upper extremity function (R2 = 0.35, p < 0.001), walking speed (R2 = 0.22, p = 0.005), and cognitive performance (R2 = 0.25, p = 0.007). Receiver Operating Characteristic curve analysis confirmed 'excellent' discriminative ability of the E/I ratio in distinguishing high and low disability. Finally, excitation superiorly correlated with the E/I ratio than overall inhibition in both hemispheres (p ≤ 0.01). Conclusion: The E/I ratio is a potential neurophysiological biomarker of disability level in MS, especially when assessed in the hemisphere corresponding to the weaker body side. Interventions aimed at increasing cortical excitation or reducing inhibition may restore E/I balance potentially stalling progression or improving function in MS.

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.

A naturalistic study comparing the efficacy of unilateral and bilateral sequential theta burst stimulation in treating major depression - the U-B-D study protocol.

BACKGROUND: Major depressive disorder (MDD) is a prevalent mental health condition affecting millions worldwide, leading to disability and reduced quality of life. MDD poses a global health priority due to its early onset and association with other disabling conditions. Available treatments for MDD exhibit varying effectiveness, and a substantial portion of individuals remain resistant to treatment. Repetitive transcranial magnetic stimulation (rTMS), applied to the left and/or right dorsolateral prefrontal cortex (DLPFC), is an alternative treatment strategy for those experiencing treatment-resistant MDD. The objective of this study is to investigate whether this newer form of rTMS, namely theta burst stimulation (TBS), when performed unilaterally or bilaterally, is efficacious in treatment-resistant MDD. METHODS: In this naturalistic, randomized double-blinded non-inferiority trial, participants with a major depressive episode will be randomized to receive either unilateral (i.e., continuous TBS [cTBS] to the right and sham TBS to the left DLPFC) or bilateral sequential TBS (i.e., cTBS to the right and intermittent TBS [iTBS] to the left DLPFC) delivered 5 days a week for 4-6 weeks. Responders will move onto a 6-month flexible maintenance phase where TBS treatment will be delivered at a decreasing frequency depending on degree of symptom mitigation. Several clinical assessments and neuroimaging and neurophysiological biomarkers will be collected to investigate treatment response and potential associated biomarkers. A non-inferiority analysis will investigate whether bilateral sequential TBS is non-inferior to unilateral TBS and regression analyses will investigate biomarkers of treatment response. We expect to recruit a maximal of 256 participants. This trial is approved by the Research Ethics Board of The Royal's Institute of Mental Health Research (REB# 2,019,071) and will follow the Declaration of Helsinki. Findings will be published in peer-reviewed journals. DISCUSSION: Comprehensive assessment of symptoms and neurophysiological biomarkers will contribute to understanding the differential efficacy of the tested treatment protocols, identifying biomarkers for treatment response, and shedding light into underlying mechanisms of TBS. Our findings will inform future clinical trials and aid in personalizing treatment selection and scheduling for individuals with MDD. TRIAL REGISTRATION: The trial is registered on https://clinicaltrials.gov/ct2/home (#NCT04142996).

Age and asymmetry of corticospinal excitability, but not cardiorespiratory fitness, predict cognitive impairments in multiple sclerosis.

Background: Cognitive impairment is a disabling and underestimated consequence of multiple sclerosis (MS), with multiple determinants that are poorly understood. Objectives: We explored predictors of MS-related processing speed impairment (PSI) and age-related mild cognitive impairment (MCI) and hypothesized that cardiorespiratory fitness and corticospinal excitability would predict these impairments. Methods: We screened 73 adults with MS (53 females; median [range]: Age 48 [21-70] years, EDSS 2.0 [0.0-6.5]) for PSI and MCI using the Symbol Digit Modalities Test and Montréal Cognitive Assessment, respectively. We identified six persons with PSI (No PSI, n = 67) and 13 with MCI (No MCI, n = 60). We obtained clinical data from medical records and self-reports; used transcranial magnetic stimulation to test corticospinal excitability; and assessed cardiorespiratory fitness using a graded maximal exercise test. We used receiver operator characteristic (ROC) curves to discern predictors of PSI and MCI. Results: Interhemispheric asymmetry of corticospinal excitability was specific for PSI, while age was both sensitive and specific for MCI. MS-related PSI was also associated with statin prescriptions, while age-related MCI was related to progressive MS and GABA agonist prescriptions. Cardiorespiratory fitness was associated with neither PSI nor MCI. Discussion: Corticospinal excitability is a potential marker of neurodegeneration in MS-related PSI, independent of age-related effects on global cognitive function. Age is a key predictor of mild global cognitive impairment. Cardiorespiratory fitness did not predict cognitive impairments in this clinic-based sample of persons with MS.

Multiple sclerosis-related heat sensitivity linked to absence of DMT prescription and subjective hand impairment but not autonomic or corticospinal dysfunction.

OBJECTIVES: Heat sensitivity (HS) describes a temporary worsening of multiple sclerosis (MS) symptoms with increased body temperature. The pathophysiology may relate to central nervous system conduction deficits and autonomic dysfunction. We conducted deep clinical phenotyping of a cohort of persons with MS to identify predictors of HS. METHODS: We recruited 59 MS participants with HS or No HS. Participants self-reported symptom severity (Hospital Anxiety and Depression Scale, Multiple Sclerosis Impact Scale, and fatigue visual analog scale) and underwent maximal exercise and transcranial magnetic stimulation testing to characterize autonomic and corticospinal function. We examined associations with HS using binomial logistic regression. RESULTS: People with HS (36/59) had significantly greater disability, depression, fatigue, and physical and psychological functional effects of MS. They also had significantly lower corticospinal excitability but not conduction. After controlling for disease-modifying therapy (DMT), disability, and disease type, self-reported difficulty using hands in everyday tasks was significantly associated with a large increase in the odds of HS. Autonomic and corticospinal dysfunction were not associated with HS. Lack of DMT use alone was also associated with a large increase in the odds of HS. DISCUSSION: Following a comprehensive assessment of plausible contributors to HS, HS was most strongly associated with lack of a DMT prescription and self-reported hand dysfunction. Surprisingly, objective measurement of autonomic and corticospinal integrity did not contribute to HS.

Lower corticospinal excitability and greater fatigue among people with multiple sclerosis experiencing pain.

Introduction: Persons with multiple sclerosis (MS) frequently report pain that negatively affects their quality of life. Evidence linking pain and corticospinal excitability in MS is sparse. We aimed to (1) examine differences in corticospinal excitability in MS participants with and without pain and (2) explore predictors of pain. Methods: Sixty-four participants rated their pain severity on a visual analog scale (VAS). Transcranial magnetic stimulation (TMS) and validated clinical instruments characterized corticospinal excitability and subjective disease features like mood and fatigue. We retrieved information on participants' prescriptions and disability status from their clinical records. Results: Fifty-five percent of participants reported pain that affected their daily functioning. Persons with pain had significantly greater fatigue and lower area under the excitatory motor evoked potential (MEP) recruitment curve (eREC AUC), a measure of total corticospinal excitability. After controlling for age, disability status, and pain medications, increased fatigue and decreased eREC AUC together explained 40% of the variance in pain. Discussion: Pain in MS is multifactorial and relates to both greater fatigue and lesser corticospinal excitability. Future work should better characterize relationships between these outcomes to develop targeted pain interventions such as neuromodulation. Summary: We examined pain in MS. Individuals with pain had higher fatigue and lower corticospinal excitability than those without pain. These outcomes significantly predicted self-reported pain.

Sex-specific disruption in corticospinal excitability and hemispheric (a)symmetry in multiple sclerosis.

Multiple Sclerosis (MS) is a neurodegenerative disease in which pathophysiology and symptom progression presents differently between the sexes. In a cohort of people with MS (n = 110), we used transcranial magnetic stimulation (TMS) to investigate sex differences in corticospinal excitability (CSE) and sex-specific relationships between CSE and cognitive function. Although demographics and disease characteristics did not differ between sexes, males were more likely to have cognitive impairment as measured by the Montreal Cognitive Assessment (MoCA); 53.3% compared to females at 26.3%. Greater CSE asymmetry was noted in females compared to males. Females demonstrated higher active motor thresholds and longer silent periods in the hemisphere corresponding to the weaker hand which was more typical of hand dominance patterns in healthy individuals. Males, but not females, exhibited asymmetry of nerve conduction latency (delayed MEP latency in the hemisphere corresponding to the weaker hand). In males, there was also a relationship between delayed onset of ipsilateral silent period (measured in the hemisphere corresponding to the weaker hand) and MoCA, suggestive of cross-callosal disruption. Our findings support that a sex-specific disruption in CSE exists in MS, pointing to interhemispheric disruption as a potential biomarker of cognitive impairment and target for neuromodulating therapies.

Task-Oriented Circuit Training as an Alternative to Ergometer-Type Aerobic Exercise Training after Stroke.

Moderate-intensity aerobic exercise training is an important treatment strategy to enhance functional recovery and decrease cardiometabolic risk factors after stroke. However, stroke related impairments limit access to ergometer-type exercise. The aims of the current study were (1) to evaluate whether our task-oriented circuit training protocol (intermittent functional training; IFT) could be used to sustain moderate-intensity aerobic workloads over a 10-week intervention period, and (2) to investigate its preliminary effects on cardiorespiratory fitness and metabolic profiles compared to constant-load ergometer-type exercise (CET). Forty chronic hemiparetic stroke survivors were randomized to receive 30 sessions of IFT or CET over ten weeks. Similar proportions of participants were randomized to IFT (7/19) and CET (9/18) sustained workloads associated with moderate-intensity aerobic exercise over the study period (p = 0.515). However, CET was associated with more substantial changes in maximal oxygen uptake (MD = 2.79 mL min-1 kg-1 CI: 0.84 to 4.74) compared to IFT (MD = 0.62 mL min-1 kg-1 CI: -0.38 to 1.62). Pre to post changes in C-reactive protein (-0.9 mg/L; p =0.017), short-term glycemia (+14.7 mol/L; p = 0.026), and resting whole-body carbohydrate oxidation (+24.2 mg min-1; p = 0.046) were observed when considering both groups together. Accordingly, IFT can replicate the aerobic intensities sustained during traditional ergometer-type exercise training. More work is needed to evaluate the dose-response effects of such task-oriented circuit training protocols on secondary prevention targets across the continuum of stroke recovery.

Probing the Brain-Body Connection Using Transcranial Magnetic Stimulation (TMS): Validating a Promising Tool to Provide Biomarkers of Neuroplasticity and Central Nervous System Function.

Transcranial magnetic stimulation (TMS) is a non-invasive method used to investigate neurophysiological integrity of the human neuromotor system. We describe in detail, the methodology of a single pulse TMS protocol that was performed in a large cohort of people (n = 110) with multiple sclerosis (MS). The aim was to establish and validate a core-set of TMS variables that predicted typical MS clinical outcomes: walking speed, hand dexterity, fatigue, and cognitive processing speed. We provide a brief and simple methodological pipeline to examine excitatory and inhibitory corticospinal mechanisms in MS that map to clinical status. Delayed and longer ipsilateral silent period (a measure of transcallosal inhibition; the influence of one brain hemisphere's activity over the other), longer cortical silent period (suggestive of greater corticospinal inhibition via GABA) and higher resting motor threshold (lower corticospinal excitability) most strongly related to clinical outcomes, especially when measured in the hemisphere corresponding to the weaker hand. Greater interhemispheric asymmetry (imbalance between hemispheres) correlated with poorer performance in the greatest number of clinical outcomes. We also show, not surprisingly, that TMS variables related more strongly to motor outcomes than non-motor outcomes. As it was validated in a large sample of patients with varying severities of central nervous system dysfunction, the protocol described herein can be used by investigators and clinicians alike to investigate the role of TMS as a biomarker in MS and other central nervous system disorders.

Canadian Platform for Trials in Noninvasive Brain Stimulation (CanStim) Consensus Recommendations for Repetitive Transcranial Magnetic Stimulation in Upper Extremity Motor Stroke Rehabilitation Trials.

Objective. To develop consensus recommendations for the use of repetitive transcranial magnetic stimulation (rTMS) as an adjunct intervention for upper extremity motor recovery in stroke rehabilitation clinical trials. Participants. The Canadian Platform for Trials in Non-Invasive Brain Stimulation (CanStim) convened a multidisciplinary team of clinicians and researchers from institutions across Canada to form the CanStim Consensus Expert Working Group. Consensus Process. Four consensus themes were identified: (1) patient population, (2) rehabilitation interventions, (3) outcome measures, and (4) stimulation parameters. Theme leaders conducted comprehensive evidence reviews for each theme, and during a 2-day Consensus Meeting, the Expert Working Group used a weighted dot-voting consensus procedure to achieve consensus on recommendations for the use of rTMS as an adjunct intervention in motor stroke recovery rehabilitation clinical trials. Results. Based on best available evidence, consensus was achieved for recommendations identifying the target poststroke population, rehabilitation intervention, objective and subjective outcomes, and specific rTMS parameters for rehabilitation trials evaluating the efficacy of rTMS as an adjunct therapy for upper extremity motor stroke recovery. Conclusions. The establishment of the CanStim platform and development of these consensus recommendations is a first step toward the translation of noninvasive brain stimulation technologies from the laboratory to clinic to enhance stroke recovery.

Walking Training Enhances Corticospinal Excitability in Progressive Multiple Sclerosis-A Pilot Study.

Background: Inflammatory lesions and neurodegeneration lead to motor, cognitive, and sensory impairments in people with multiple sclerosis (MS). Accumulation of disability is at least partially due to diminished capacity for neuroplasticity within the central nervous system. Aerobic exercise is a potentially important intervention to enhance neuroplasticity since it causes upregulation of neurotrophins and enhances corticospinal excitability, which can be probed using single-pulse transcranial magnetic stimulation (TMS). Whether people with progressive MS who have accumulated substantial disability could benefit from walking rehabilitative training to enhance neuroplasticity is not known. Objective: We aimed to determine whether 10 weeks of task-specific walking training would affect corticospinal excitability over time (pre, post, and 3-month follow-up) among people with progressive MS who required walking aids. Results: Eight people with progressive MS (seven female; 29-74 years old) with an Expanded Disability Status Scale of 6-6.5 underwent harness-supported treadmill walking training in a temperature controlled room at 16°C (10 weeks; three times/week; 40 min at 40-65% heart rate reserve). After training, there was significantly higher corticospinal excitability in both brain hemispheres, reductions in TMS active motor thresholds, and increases in motor-evoked potential amplitudes and slope of the recruitment curve (REC). Decreased intracortical inhibition (shorter cortical silent period) after training was noted in the hemisphere corresponding to the stronger hand only. These effects were not sustained at follow-up. There was a significant relationship between increases in corticospinal excitability (REC, area under the curve) in the hemisphere corresponding to the stronger hand and lessening of both intensity and impact of fatigue on activities of daily living (Fatigue Severity Scale and Modified Fatigue Impact Scale, respectively). Conclusion: Our pilot results support that vigorous treadmill training can potentially improve neuroplastic potential and mitigate symptoms of the disease even among people who have accumulated substantial disability due to MS.

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).

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.

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.

Use of infrared thermography in Quarter Horse submitted to team roping / Uso da termografia infravermelha em equinos da raça Quarto de Milha submetidos à prova de laço em dupla

This study aimed to verify whether the body and local temperatures change after high-intensity, short-duration exercise (team roping) and whether different pieces of training influence these changes. To this end, twelve animals, males and females, aged 3-6 years, with an average weight of 450 kg, were used. The horses were divided into two groups: regular training (RTG) and sporadic training (STG). The surface temperatures were assessed using a specific thermal camera. Temperatures of the ocular, thoracolumbar, distal tendon (thoracic and pelvic limbs) and croup regions were measured 30 min before, immediately after, and one, two, six and 24 hours after competition simulation. In the RTG, there was an increase in surface eye temperature two hours after exercise, returning to baseline level 24 hours later. In the STG, increase in eye temperature occurred immediately after exercise and returned to baseline level two hours later. Temperature of the pelvic limb tendons and croup (right side) rose immediately after exercise and did not return to baseline level 24 hours later. Team roping exercise increased the surface temperature of the distolateral thoracic and pelvic limb, croup and thoracolumbar regions in both groups and the eye temperature in the STG. Training frequency influenced the surface temperature profile in the distolateral pelvic limb, croup and thoracolumbar regions.(AU)

Os objetivos do presente estudo foram verificar se as temperaturas corpóreas e locais se alteram após exercício de alta intensidade e curta duração (prova de laço em dupla) e se treinamentos distintos podem influenciar nestas alterações. Foram utilizados 12 animais, machos e fêmeas, com idade entre 3 e 6 anos e peso médio de 450kg. Os animais foram divididos em dois grupos: treino regular (GTR) e treino esporádico (GTE). As aferições da temperatura por meio de termografia infravermelha foram feitas por uma câmera termal específica. As medições das temperaturas das regiões ocular, toracolombar, tendíneas distais (membros torácicos e pélvicos) e garupa foram realizadas 30 minutos antes, imediatamente depois, uma, duas, seis e 24 horas após a simulação de competição. No GTR houve aumento de temperatura ocular duas horas após o exercício, retornando ao basal apenas 24 horas depois. No GTE o aumento ocorreu imediatamente após o exercício e retornando ao basal duas horas depois. As temperaturas da região dos tendões dos membros pélvicos e garupa (lado direito) elevaram-se imediatamente após o exercício e não retornaram ao basal após 24 horas. O exercício de laço em dupla aumentou as temperaturas superficiais nas regiões distolateral de membros torácicos e pélvicos, garupa e região toracolombar de ambos os grupos e da temperatura ocular do GTE. A frequência de treinamento influenciou o perfil de temperatura superficial na região distal de membros pélvicos, garupa e toracolombar.(AU)

Synergistic Benefits of Combined Aerobic and Cognitive Training on Fluid Intelligence and the Role of IGF-1 in Chronic Stroke.

BACKGROUND: Paired exercise and cognitive training have the potential to enhance cognition by "priming" the brain and upregulating neurotrophins. METHODS: Two-site randomized controlled trial. Fifty-two patients >6 months poststroke with concerns about cognitive impairment trained 50 to 70 minutes, 3× week for 10 weeks with 12-week follow-up. Participants were randomized to 1 of 2 physical interventions: Aerobic (>60% VO2peak using <10% body weight-supported treadmill) or Activity (range of movement and functional tasks). Exercise was paired with 1 of 2 cognitive interventions (computerized dual working memory training [COG] or control computer games [Games]). The primary outcome for the 4 groups (Aerobic + COG, Aerobic + Games, Activity + COG, and Activity + Games) was fluid intelligence measured using Raven's Progressive Matrices Test administered at baseline, posttraining, and 3-month follow-up. Serum neurotrophins collected at one site (N = 30) included brain-derived neurotrophic factor (BDNF) at rest (BDNFresting) and after a graded exercise test (BDNFresponse) and insulin-like growth factor-1 at the same timepoints (IGF-1rest, IGF-1response). RESULTS: At follow-up, fluid intelligence scores significantly improved compared to baseline in the Aerobic + COG and Activity + COG groups; however, only the Aerobic + COG group was significantly different (+47.8%) from control (Activity + Games -8.5%). Greater IGF-1response at baseline predicted 40% of the variance in cognitive improvement. There was no effect of the interventions on BDNFresting or BDNFresponse; nor was BDNF predictive of the outcome. CONCLUSIONS: Aerobic exercise combined with cognitive training improved fluid intelligence by almost 50% in patients >6 months poststroke. Participants with more robust improvements in cognition were able to upregulate higher levels of serum IGF-1 suggesting that this neurotrophin may be involved in behaviorally induced plasticity.

Prolonged cortical silent period is related to poor fitness and fatigue, but not tumor necrosis factor, in Multiple Sclerosis.

OBJECTIVE: Poor fitness among people with Multiple Sclerosis (MS) aggravates disease symptoms. Whether low fitness levels accompany brain functioning changes is unknown. METHODS: MS patients (n = 82) completed a graded maximal exercise test, blood was drawn, and transcranial magnetic stimulation determined resting and active motor thresholds, motor evoked potential latency, and cortical silent period (CSP). RESULTS: Sixty-two percent of participants had fitness levels ranked below 10th percentile. Fitness was not associated with disability measured using the Expanded Disability Status Scale (EDSS). Regression analyses revealed that, cardiorespiratory fitness, when controlling for disease demographics, contributed 23.7% (p < 0.001) to the model explaining variance in CSP. Regression analysis using cardiorespiratory fitness and CSP as predictors showed that CSP alone explained 19.9% of variance in subjective fatigue (p = 0.002). Tumor necrosis factor was not associated with any variable. CONCLUSION: Low fitness was associated with longer CSP in MS. Longer CSP was, in turn, related to greater MS fatigue. SIGNIFICANCE: MS patients had extremely low levels of cardiorespiratory fitness. Poor fitness predicted longer CSP, a marker of greater intracortical inhibition, which was linked to MS fatigue. Future research should examine whether aerobic training could shorten CSP and potentially lessen inhibition of cortical networks.

Asymmetry of Brain Excitability: A New Biomarker that Predicts Objective and Subjective Symptoms in Multiple Sclerosis.

OBJECTIVES: Investigate whether asymmetrical corticospinal excitability exists in Multiple Sclerosis (MS) and its association with MS symptoms. METHODS: Bilateral resting and active motor thresholds (RMT, AMT) were gathered using transcranial magnetic stimulation among 82 MS patients. Corticospinal excitability (CSE) asymmetry was expressed as the ratio between weaker and stronger sides' RMT and AMT. Stronger and weaker side was determined by pinch and grip strength. We examined whether CSE asymmetry predicted symptoms. RESULTS: AMT asymmetry ratio revealed atypical CSE asymmetry whereby the hemisphere associated with the weaker hand was more excitable in early MS. After controlling for MS disease demographics, shifting of CSE asymmetry towards greater excitability in the stronger side significantly predicted more severe symptoms including Expanded Disease Severity Scale, nine-hole peg test, cognitive processing speed, walking speed, heat sensitivity, fatigue, and subjective impact of MS. CONCLUSION: CSE asymmetry significantly predicted the severity of MS-related physical and objective cognitive symptoms. The phenomenon may be related to neuroinflammation-mediated hyperexcitability. Shifting of asymmetry toward less excitability on the weaker side may suggest the onset of a more neurodegenerative phase of the disease. SIGNIFICANCE: Shifting of hemispheric excitability, detected using a CSE asymmetry ratio, may be a useful biomarker to track disease progression and understand the benefits of treatments.

Avaliação da lactatemia e das enzimas musculares de equinos Quarto de Milha submetidos à prova de laço em dupla com diferentes tipos de treinamento / Evaluation of lactatemia and muscle enzymes in Quarter Horses subjected to team ropping with different types of training

O objetivo do trabalho foi avaliar a influência de diferentes tipos de treinamento sobre o condicionamento físico de equinos por meio da determinação do lactato sanguíneo e da atividade sérica de creatina quinase, aspartato aminotransferase e lactato desidrogenase após exercício físico de alta intensidade e curta duração. Amostras de sangue venoso foram obtidas de 16 equinos da raça Quarto de Milha, divididos em dois grupos: grupo de treinamento regular (GTR) e grupo de treinamento esporádico (GTE), em sete diferentes momentos: 30 minutos antes do exercício (M0), imediatamente após (M1), 30 minutos (M2), uma (M3), duas (M4), seis (M5) e 24 (M6) horas após o exercício. Para a análise estatística, os dados foram testados quanto à normalidade e homogeneidade de variâncias. Para comparar os grupos e os momentos em cada grupo foram utilizados testes paramétricos (ANOVA) para a análise das atividades séricas das enzimas musculares e não paramétricos (Mann-Whitney e Friedmann) para a análise do lactato sanguíneo (P<0,05). Não houve diferença significativa entre os grupos para nenhuma variável. No entanto, dentro dos grupos experimentais foi possível observar diferenças significativas entre os momentos avaliados, em relação ao lactato e à LDH. No GTE, foram observadas diferenças significativas quanto ao lactato, entre o M0 e o M1, com valores respectivos de 0,90 mmol/L (mín. 0,8 - máx. 1,6) e 3,65mmo/L (mín. 1,0 - máx. 5,7) e quanto à LDH, onde os valores descritos no M6 diferiram significativamente de M0, M1, M2, M3 e M4. No GTR, diferenças significativas entre os momentos experimentais foram observadas em relação à LDH, sendo que os valores observados no M6 foram os menores e diferiram significativamente daqueles encontrados no M1, M2, M3 e M4. Em conclusão, não houve diferença entre o condicionamento físico dos animais treinados regularmente e aqueles treinados esporadicamente. A baixa magnitude das elevações das concentrações de CK, AST e LDH após o exercício e o rápido retorno aos valores basais, inclusive do lactato, observados em ambos os grupos, sugere que todos os animais avaliados estavam condicionados e aptos a realizar tal atividade física.(AU)

The aim of this study was to evaluate the influence of different types of training on physical fitness through the determination of blood lactate and serum creatinine kinase, aspartate aminotransferase, and lactate dehydrogenase activity after high intensity and short duration physical exercise. Venous blood samples were obtained from 16 Quarter Horses, divided into two groups: the regular training group (GTR) and sporadic training group (GTE), in seven different moments: 30 minutes before exercise (M0), immediately after the exercise (M1), 30 minutes (M2), one hour (M3), two hours (M4), six hours (M5) and 24 hours (M6) after the exercise. For statistical analysis, data was tested for normality and homogeneity of variances. To compare the groups and times in each group, parametric tests (ANOVA) were used for muscular enzymes activity and not parametric tests (Mann-Whitney and Friedmann) were used to analyze blood lactato (P<0.05). There was no significant difference between groups for any variable. However, within the experimental groups it was possible to observe significant differences between the evaluated moments, in relation to lactate and LDH. In the GTE, significant differences were observed for lactate between M0 and M1, with respective values ​​of 0.90 mmol/L (min. 0.8, max. 1.6) and 3.65 mmol/L (min. 1.0, max. 5,7) and for LDH, where the values ​​described in M6 differed significantly from M0, M1, M2, M3 and M4. In the GTR, significant differences between the experimental moments were observed in relation to LDH, and the values ​​observed in M6 were the lowest and differed significantly from those found in M1, M2, M3 and M4. In conclusion, there was no difference between the fitness of animals regularly trained and those trained sporadically. The low magnitude of elevations of serum CK, AST and LDH activity after exercise and the quick return to baseline values, including the blood lactate observed in both groups, suggest that all of evaluated animals were conditioned and able to perform such physical activity.(AU)